Note: Descriptions are shown in the official language in which they were submitted.
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SHEET AND LIQUID COMBINATION SYSTEMS FOR
DERMAL DRUG DELIVERY
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No.
61/411,728 filed
November 9, 2010, entitled "SHEET AND LIQUID COMBINATION SYSTEMS FOR
DERMAL DRUG DELIVERY," which is incorporated herein by reference in its
entirety.
BACKGROUND
[0002] Dermal drug delivery systems (comprising drug formulations applied on
the skin or
mucosa) are widely used in treating medical conditions not only in the
"surface tissues" such
as skin or mucosa but also in deeper tissues such as musculoskeletal tissues.
Some dermal
drug delivery systems, such as fentanyl patches, even deliver drugs targeted
for the central
nervous system.
[0003] Almost all commercially available dermal drug delivery products are
"one part"
products, meaning the user does not need to combine or assemble two or more
parts prior to
or during the application. Such "one part" topical products include creams,
ointments,
patches, and sprayed-on formulations.
[0004] "One part" products, as opposed to multiple-part products, are
convenient to use, but
have limitations. If a drug has poor stability when exposed to a necessary
excipient,
incorporating the drug and the excipient into a "one part" product can make
the drug
unstable. For example, tetracaine base is subject to hydrolytic degradation
when exposed to
water, so a water-containing cream makes the tetracaine in it unstable and
thus likely needs to
be refrigerated to achieve the desired shelf life. In other circumstances, it
may be desirable to
have pre-determined differential onset times of effects for two active
ingredients in the same
product, but putting the two active ingredients in a "one part" product makes
achieving the
desired effect onset time differential difficult.
[0005] In summary, there are situations in which it is desirable to have a
dermal drug
delivery system with two or more components, such as a waterless solid sheet
impregnated
with a drug (and optionally with cxcipients) and a water-containing liquid
solvent vehicle for
dissolving the drug and delivering the drug via transdermal permeation, that
are assembled or
joined just before or during the application.
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DETAILED DESCRIPTION
[0006] In some embodiments of the current invention, the dermal drug delivery
system
comprises two components: the first component comprises a sheet of a solid and
flexible
material impregnated with certain ingredient(s); the second component
comprises a vehicle
liquid comprising a solvent. The second component may optionally further
comprise other
ingredients. These two components are stored separately and joined either
shortly before or
at the time of application. This system is generally referred to as a Sheet
and Liquid
Combination system hereafter. To use the system, the vehicle liquid is applied
either on the
target skin area or on the sheet, and the sheet is then applied on the target
skin area so that the
vehicle liquid is either between the sheet and the skin, absorbed into the
solid sheet in whole
or in part, or at least partially absorbed into the sheet and partially
present between the sheet
and the skin. After the sheet and the vehicle liquid are combined in this pre-
designed way,
the ingredients in the sheet and in the vehicle liquid are joined to form a
combined (new)
formulation that is capable of delivering the drug through the skin at the
desired rates.
[0007] At least one of the two components comprises a drug (active
ingredient). In some of
the embodiments, each component alone is not able to deliver the drug at a
desired rate, but
the combination is. In other embodiments, one of the two components alone may
be able to
deliver the drug at a desired rate, but the other component provides another
desirable
property. For instance, a low viscosity drug solution may be able to deliver
the drug into the
skin at a desired rate if it is kept on the skin for long enough time.
However, it is difficult to
keep a low viscosity solution on skin for long time. Therefore, a system
comprising a low
viscosity drug solution in one component and a sheet with a liquid retention
layer and a
barrier film (discussed in further detail below) as another component may be
used to keep the
drug solution on the skin for long time.
[0008] It is noted that, as used in this specification and the appended
claims, singular forms
of "a," "an," and "the" include plural referents unless the content clearly
dictates otherwise.
[0009] "Vehicle liquid", or "liquid" in the Sheet and Liquid Combination
system, means a
liquid comprising a vehicle solvent system that is necessary to transdermally
deliver the drug
at rates high enough to achieve the desired effect(s). Vehicle liquid can be a
free flowing
liquid, a viscous liquid, liquid soaked in an absorbent sheet, a water-
containing foam, or
liquid in a solidified gel such as a hydrogel. Vehicle liquid may comprise
only a single
ingredient such as water, or multiple ingredients such as water, thickening
agents, adhesion
agents, etc. Vehicle liquid may have a color so that it is easier to see where
it is spread on the
skin or the sheet. In some of the embodiments of the current invention, the pH
of the vehicle
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liquid can be important to the rate of delivery of the drug into the skin. In
such embodiments,
the pH of the vehicle liquid should be such that the vehicle liquid has
sufficient solubility for
the drug to facilitate the delivery of the drug at the desired rate, and (when
the drug is an
ionic substance) produces ratio(s) of unionized to ionized drug molecules in
the vehicle liquid
that can facilitate the permeation of the drug into human skin. In some
embodiments of the
current invention the pH of the vehicle liquid, initially or during the drug
delivery process,
needs to be such that a significant portion of the drug molecules dissolved in
the vehicle
liquid is in the unionized form, because for many drugs the unionized
molecules can
permeate normal human skin faster than the ionized ones. In some embodiments
of the
current invention, the drug to be delivered is a base and the pH of the
vehicle liquid is not
more than 1.5 pH units lower than the pKa of the drug, and may be not more
than 1.0 unit
lower than the pKa of the drug. In another embodiment, the vehicle liquid has
an initial pH
more than 1.0 pH unit lower than the pKa of the drug, but it has a weak pH
buffer capacity so
that when it is in contact with the sheet, the drug and/or a pH modifying
agent impregnated in
the sheet can dissolve into it and increase the pH to not more than 1.0 pH
unit lower than the
pKa of the drug. In another embodiment, the vehicle liquid (such as distilled
water) has a
weak pH buffer capacity. When such a vehicle liquid and the solid sheet are
joined, the
substance(s) in the solid sheet determines the pH of the liquid after the
substance(s) in the
solid sheet dissolves into the liquid. For example, the vehicle liquid can
have a pH of about
7.0 but very weak pH buffer capacity (distilled water is such a vehicle
liquid). When it is
brought in contact with a sheet impregnated with a sufficient amount of
tetracaine base per
cm2, some of the tetracaine (a base) dissolves into the vehicle liquid and
increases its pH to
7.5 or higher. As a result, the pH of the vehicle liquid is increased
sufficiently during the
application period to facilitate fast permeation of the tetracaine into the
skin. In some
embodiments, the vehicle liquid is contained in a spray bottle and is sprayed
onto the target
skin area or the sheet prior to the application of the sheet on the target
skin area. In other
embodiments, the vehicle liquid is contained in a bottle with an applicator,
such as, without
limitation, a brush, on the lid, or separate from the lid, but capable of
being attached to the
lid, and is applied onto the target skin area or the sheet with the applicator
prior to the
application of the sheet on the target skin area. In other embodiments, the
vehicle liquid is a
viscous aqueous solution contained in a squeeze bottle with a long nozzle for
dispensing and
spreading the vehicle liquid on the skin or solid sheet. In some other
embodiments, the
vehicle liquid is essentially water (may contain color agent or preservative),
so the pH of the
vehicle liquid will be altered and determined by the substance(s) impregnated
in the sheet
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after the vehicle liquid and the solid sheet are joined and the substance(s)
gets dissolved in
the liquid.
[0010] A "layer of vehicle liquid" means a continuous layer of the vehicle
liquid, a
substantially two dimensional presence but not necessarily continuous layer of
the vehicle
liquid (e.g., densely populated fine droplets of the vehicle liquid), or the
vehicle liquid
existing in a substantially two dimensional sheet of material (e.g. absorbed
into a sheet of
material to form a "wet" sheet).
[0011] "Sheet," as used in describing the Sheet and Liquid Combination system
of the
current invention, means a sheet of solid material such as a paper, film,
tape, fabric, sponge,
or a combination thereof, that is impregnated with at least one of the
ingredients necessary for
the dermal drug delivery. The sheet can have a moisture vapor transfer rate
(MVTR) that is
very low, so that it keeps almost all of the water in the vehicle liquid
placed between it and
the skin for the entire duration of the application period. Alternatively, the
sheet can have a
pre-determined MVTR that allows water in the vehicle liquid to evaporate
through it at rates
such that sufficient amount of water in the vehicle liquid placed between it
and the skin stays
long enough to deliver the desired amount of the drug, but by the end of the
application,
enough of the water has evaporated so that there is minimal or no residue
water left on the
skin. This pre-determined MVTR is defined as "dry-ending MVTR".
[0012] In some of the embodiments of the current invention, once the sheet and
the vehicle
liquid are joined and applied on the skin, the solvent in the vehicle liquid
is present long
enough to deliver a predetermined amount of the drug impregnated in the sheet
into the skin.
In such embodiments, the sheet's MVTR must be low enough to keep the solvent
present
long enough to deliver the predetermined amount of the drug.
[0013] "MVTR" means moisture vapor transfer rate, as measured with methods
commonly
used in the industry, such as those used by 3M Co. When a sheet is said to
have a certain
MVTR value, it means at least some part of the sheet has that MVTR value, and
potentially
that much or most of the sheet's area has that MVTR value, but it does not
necessarily mean
that the entire sheet area has that MVTR value.
[0014] One of the shortcomings of traditional dermal drug delivery patches is
their finite
sizes and shapes. For treating conditions with irregular and variable target
skin areas, the
fixed shape and size can be a problem. For example, the skin area suffering
from pain
associated with post herpetic neuralgia can have various shapes and sizes, so
that covering it
with a patch with fixed area and shape is difficult or impossible. To mitigate
this problem,
Lidoderm Patch (Endo Pharmaceutical) is often cut with scissors to fit the
lesion area, which
A
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can be inconvenient to the user. To address this problem, in one of the
embodiments of the
current invention, the drug-impregnated sheet is in the shape of a roll and
may have a pattern
of perforation or partial-cut lines that allow the user to use just hands to
easily tear a piece of
the sheet with the shape and size that approximately fits the target skin
area. Alternatively,
the sheet is not in a roll but in the form of a large sheet with a pattern of
perforation or
partial-cut lines, for the same purpose. Of course, the sheet can also simply
be a large sheet,
and the user can cut it into the size and shape desired to fit the application
area.
[00151 In some embodiments of the current invention, the sheet has a "lateral
diffusion
function" or comprises a "lateral diffusion layer". The lateral diffusion
layer is typically a
layer of material very absorbent to the vehicle liquid, such as water. When a
droplet of the
vehicle liquid is placed on the lateral diffusion layer, it is quickly
absorbed into the layer and
spread laterally to cover an area much larger than the initial size, as
measured by cross-
sectional area, of the droplet. (When a drop of water is placed on a Kleenex
tissue, it will
quickly spread laterally into a circle whose diameter is much larger than the
diameter of the
initial water drop. However, a drop of water placed on an aluminum foil will
not diffuse
much laterally. In this comparison, the Kleenex tissue has the lateral
diffusion function and it
or a material with similar lateral diffusion function may be used as a lateral
diffusion layer in
a sheet, while the aluminum foil does not have the lateral diffusion function
and cannot be
used as a lateral diffusion layer in a sheet). The lateral diffusion layer is
typically the layer in
the sheet that is in contact with the vehicle liquid when the combination of
the sheet and the
vehicle liquid is applied on the skin. The lateral diffusion layer can make
sure that the vehicle
liquid can evenly spread over the desired area under the sheet, even if the
initial application
of the vehicle liquid on the skin or the sheet is not very even. For example,
water as the
vehicle liquid can be sprayed on the skin to cover the target skin area with
densely populated
water beads, but not quite a continuous layer of water. The lateral diffusion
layer applied over
the water beads will quickly absorb the water beads. The absorbed water will
then quickly
spread laterally, so that the entire sheet area will have even water
distribution. Many
absorbent materials may be used as the material for the lateral diffusion
layer, including
gauze (woven or non-woven), paper, foam (especially open-cell foam), cloth,
and other fabric
materials. For example, the fabric (gauze) layer in the fabric-tape laminate
sheets in many of
the following Examples is the lateral diffusion layer.
[0016] Unless specified otherwise, when a tape-fabric or film-fabric laminate
sheet is said to
be "applied to the skin," it means the sheet is applied in such a way that the
fabric side of the
laminate is the side that is in direct contact with the skin and the applied
vehicle liquid.
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100171 A lateral diffusion layer can also be useful in the manufacturing
process. It is
generally much easier to dispense precise volumes of solution on a sheet of
material than cast
a thin layer of solution with precise thickness on a sheet of material. If the
droplets of the
solution containing the drug (and optionally the fastening agent) are
dispensed on a lateral
diffusion layer (in this case the lateral diffusion layer is very absorbent to
the solution
containing the drug and fastening agent), the solution is quickly absorbed
into the layer,
spread laterally, and reach even distribution within the layer within minutes
or even seconds.
As a result, the drug and the fastening agent dissolved in the solution also
reach even
distribution within the lateral diffusion layer. The volatile solvent in the
lateral diffusion
layer is then evaporated off, leaving evenly distributed drug and fastening
agent in the lateral
diffusion layer (and thus the sheet). For example, the gauze layer in the
gauze-tape laminate
sheet in Examples 3-5, among others, functioned as the lateral diffusion layer
for the
manufacturing of the sheet impregnated with the drug and fastening agent.
[0018] Since the lateral diffusion layer is absorbent to the vehicle liquid,
it typically has very
high MVTR (moisture vapor transfer rate). Therefore, in order to maintain
water in the
vehicle liquid between the sheet and skin for sufficient time to deliver the
desired amount of
the drug into the skin, the lateral diffusion layer is often laminated with a
"MVTR control
layer" to form a sheet that has both the lateral diffusion function and proper
MVTR.
Typically, the "MVTR control layer" is a layer of material that has much lower
MVTR than
that of the lateral diffusion layer and thus dominantly determines the overall
MVTR for the
sheet. The MVTR control layer is typically a layer of plastic film or tape
with desired MVTR.
For example, the 3M 9832 polyurethane tape in Example 4 and 5 is the MVTR
control layer
in the laminate sheet.
[0019] The MVTR control layer can also be or comprise a barrier film with
adequate MVTR.
In the current invention, the phrase "barrier film" means a film with MVTR
lower than 5,000
g/m2/24 hour, and in some instances lower than 2,000 g/m2/24 hour. It should
be noted that
many tapes used in the current invention, such as 3M 9832, 3M 9834 tapes,
comprise a
barrier film layer. A tape is typically a film coated with a layer of
adhesive.
[0020] The fabric (lateral diffusion) layer and the MVTR control layer can be
conveniently
laminated by using the layer of adhesive coated on MVTR control layer, if the
MVTR control
layer is a tape with adhesive coating on one side. For example, the 3M9832
tape is a
polyurethane film with one side coated with a layer of adhesive. As shown in
some of the
examples below, a layer of fabric can be placed on the adhesive side of the
tape to form a
fabric/barrier film laminate. This adhesive lamination process is relatively
easy to complete,
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and use of medical-grade tape should helps to assure safety in human use.
However, the
inventor surprisingly found evidence suggesting that some adhesives used for
lamination
(lamination adhesives) interact with the tetracaine formulation in the sheet
(chemically or
physically) so that the anesthetizing ability of the sheet could be
compromised after long term
storage. Further, the inventor determined that one of the lamination adhesives
tested has
much less or no tendency to compromise the anesthetizing ability. To avoid the
potential
problem of adverse interaction between the lamination adhesive and the drug
formulation, in
some of the embodiments of the current invention, the fabric is laminated to
the barrier film
(MVTR control layer) by heat.
[0021] It should be noted that for any given pair of barrier films and fabric
materials, there
may or may not exist a window of heating temperature and duration in a heat
lamination
process that may be used to successfully laminate the two materials without
damaging the
barrier film.
[0022] Through experimentation, the inventor found a window of heating
temperature/duration that allows a rayon polyester fabric (a preferred fabric
for many
embodiments of the current invention) and a polyurethane film (a preferred
MVTR control
layer material) to be securely laminated together with heat without damaging
either the fabric
or the film.
[0023] "Fabric layer" or "fabric" means a material or a layer of material that
is absorbent of
water or water based solution, including woven and non-woven materials. For
example, a
layer of non-woven rayon-polyester blend material as that used in some of the
examples
below is a fabric layer. In contrast, wax-coated paper is not "fabric" by the
definition herein
because it is not absorbent to water.
[0024] In some of the embodiments, the sheet in the sheet and liquid
combination system can
have a liquid retention layer for keeping the vehicle liquid on the skin for
long enough time to
deliver the desired amount of the drug. As can be seen in some of the examples
below,
maintaining water on the skin for long enough time can be very important in
delivering
sufficient amount of drug into the skin to achieve desired clinical effect. A
liquid retention
layer, such as a fabric layer in a fabric-barrier film laminate sheet, can
absorb the vehicle
fluid and keep it relatively evenly available to the skin for the desired
length of time. A liquid
retention layer can have the lateral diffusion function and can be the lateral
diffusion layer at
the same time.
[0025] In some embodiments, the drug is incorporated into the MVTR control
layer itself,
and the lateral diffusion layer is not used. For example, tetracaine can be
incorporated into a
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barrier film which itself is the MVTR control layer. The means of
incorporating tetracaine
into barrier film includes, without limitation, diffusing tetracaine into the
barrier film and
blending tetracaine into the monomers to be polymerized into the barrier film.
For example,
in Example 38, tetracaine was incorporated into the polyurethane film by
diffusion. When
this tetracaine-impregnated barrier film is used with a viscous aqueous
solution (vehicle
liquid), enough tetracaine was delivered into the skin to produce deep skin
anesthesia. Drugs
other than tetracaine, such as anti-infection agents, may also be incorporated
into the MVTR
control layer with similar methods. In those embodiments, the drug impregnated
barrier film
constitutes the sheet in the sheet and liquid combination system of the
current invention.
[00261 "Fastening agent" means a substance that "fastens" a drug or an
excipient on the
sheet. Without the fastening agent, the drug or the excipient impregnated in
the sheet may be
only loosely held by the sheet and can be unintentionally removed from the
sheet when the
sheet is shaken, bent, touched, or rubbed. Substances that can bind with both
the sheet and the
drug or excipient can function as fastening agents. Such substances include
but are not
limited to polyvinylpyrrolidone (PVP), poly vinyl alcohol (PVA), ethyl
cellulose, hydroxy
propyl cellulose, carrageenan, and gum Arabic. However, in some embodiments,
the drug is
incorporated into the barrier film polymer itself (see Example 38). In those
embodiments, a
fastening agent may not be necessary.
[00271 "Adhesion agent" is a substance capable of facilitating the adhesion
between the skin
and the sheet. It can initially exist in the vehicle liquid. It can also
initially exist in the sheet,
and dissolve into the vehicle liquid when the vehicle liquid and the sheet are
brought into
contact. Substances that are soluble in the vehicle liquid and increase the
vehicle liquid's
adhesion to skin or to the sheet can be used as adhesion agents. Such
substances include, but
are not limited to, PVP, PVA, poly acrylic polymers such as the Carbomer
polymers
marketed by Noveon (e.g Carbopol 981), xantham gum, and gum Arabic. Adhesion
agent
can also be a combination of two or more substances. For example,
polyvinylpyrrolidone-
glycerin mixture and polyvinylpyrrolidone-poly ethylene glycol 400 mixture,
with
appropriate polyvinylpyrrolidone percentages, can be used as adhesion agents.
[0028] "Normal human skin" means human skin with an intact stratum comeum
layer and
normal skin temperature (typically in the range of 30-36 C). Normal human skin
can include
skin that is suffering from a disease or pain but has an intact stratum
corneum layer.
[0029] "Normal ambient conditions" means temperatures in the range of 20-35 C
and
relative humidity in the range of 0 to 80%.
0
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[0030] The phrases "anesthesia in skin", "anesthetized skin", "numbness", and
the like, mean
the skin is anesthetized at least to the extent that it feels obviously numb
when it is scratched
or poked with the end of a straightened paper clip. This skin numbing effect
can be observed
in a single human subject (such as in some of the Examples) or can be observed
in a formal
clinical trial. Since there are often outliers in human testing, this term is
used to denote that in
a formal clinical trial, at least 70% of the subjects in a group of at least
24 subjects have the
effect. Alternatively, the definition can be that the effect is statistically
significant according
to the US Food and Drug Administration's definition at the time of testing.
[0031] The term "free of water" when used to describe an environment or medium
(such as
the aforementioned solid sheets) in which exists tetracaine or other drugs
that are subject to
hydrolytic degradation, means that the environment does not have a sufficient
amount or
concentration of water to cause the tetracaine or said other drugs to lose
more than 2% per
year to hydrolytic degradation at room temperature.
[0032] The term "subject to hydrolytic degradation" means that a drug, in a
formulation
containing a concentration of water which is sufficient to deliver the drug at
sufficient rates to
achieve the desired clinical effect, is subject to a hydrolytic degradation
process with high
enough rates so that a shelf life of at least one year at room temperature (by
US FDA methods
and definition) cannot be obtained.
[0033] The term "appropriate quantity" when referring to the quantity of the
vehicle liquid
applied on the skin or sheet means a quantity of the vehicle liquid that is
high enough and can
last long enough to allow a sufficient amount of the drug to be delivered
transdermally into
the skin to achieve the desired clinical effect(s), but not so high as to
cause problems such as
overflow or running. The "appropriate quantity" can depend on the MVTR of the
particular
sheet, among other factors, and can be in the range of 2 to 200 milligrams per
cm2 (mg/cm2),
including the range of 10 to 50 mg/cm2, and including the range of 20 to 30
mg/cm2.
[0034] The phrase "between the skin and the sheet", and the like, when
referring to the
position of the vehicle liquid relative to the skin and the sheet means the
vehicle liquid is
between the skin and the sheet and includes situations in which the vehicle
liquid is applied
onto or absorbed into the sheet, or partially absorbed into the sheet and
partially present
between the sheet and the skin, and the sheet is applied on the skin.
[0035] "Target skin area" in general means an area of human (or other mammal)
skin into
which the delivery of the drug is expected to produce the desired clinical
effect(s). For
anesthetizing the skin before painful procedures, reducing the pain associated
with shingles,
and other pain associated with diseases or trauma of the skin, the target skin
area can be the
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skin area suffering from the pain. For musculoskeletal pain, the target skin
area can be the
skin area under or adjacent to which the musculoskeletal pain exists. Target
skin area can
also be the skin area over a "trigger point", a hyperirritable spot in the
tissue (usually muscle
tissue) that sometimes can cause pain quite distant from the trigger point
itself. Target skin
area can also be a skin area over a tissue into which physicians would inject
a local anesthetic
or other drugs to reduce pain (e.g., skin area over the site into which
physicians inject
lidocaine to reduce shoulder pain). Target skin area can be an area of
diseased or normal
skin.
[0036] The term "properly adhered", "proper adhesion", and the like, when
referring to the
adhesion of the sheet on human skin, means that the adhesion is such that the
sheet can stay
on a normal human skin area under normal ambient conditions for at least 15
minutes no
matter how the skin area is positioned (e.g., face up, face down, or at an
angle such that the
sheet is vertical to the ground).
[0037] "Rubbing alcohol" in the Examples means Western Family brand rubbing
alcohol
which contains 70% isopropyl alcohol by volume.
[0038] "Tetracaine" can mean tetracaine base or a salt of tetracaine (e.g.
tetracaine
hydrochloride). Similarly, any drug listed in this disclosure includes its
salt(s).
[0039] "Pain reduction" can mean the reduction of pain sensed by a human being
in general.
Pain reduction can also mean statistically significant reduction of pain as
measured by
methods commonly used in clinical trials employing commonly used patient
selection criteria
and test conditions. Such methods include, without limitation, the visual
analog pain scale
method.
[0040] Many drugs can be delivered using the systems and methods of the
current invention.
These drugs include, but are not limited to, local anesthetics such as
lidocaine, tetracaine,
prilocaine, bupivacaine, benzocaine, ropivacaine, etidocaine, mepivacaine,
dibucaine; non-
steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac and ketoprofen;
capsaicin;
drugs that are used to treat neuropathic pain such as N-methyl-D-asparate
(NMDA) receptor
antagonists (e.g. gabapentin) and ketamine. In some systems of the current
invention, the
drugs which particularly benefit from the systems and methods of the current
invention are
those which are subject to hydrolytic degradation when in contact with water.
[0041] In some embodiments of the current invention, a system for delivering a
local
anesthetic agent into human skin comprises a first component and a second
component. The
first component comprises a sheet of a solid and flexible material and is
impregnated with a
local anesthetic agent. If the local anesthetic agent is an ester type local
anesthetic agent such
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as tetracaine or benzocaine, the sheet is free of water because these local
anesthetics are
subject to hydrolytic degradation. The sheet can also be free of water even if
the local
anesthetic is the amide type which is not subject to significant hydrolytic
degradation. But for
ester types, being free of water is more important. The second component
comprises a vehicle
liquid comprising water. To use the system to deliver the local anesthetic
into human skin or
skin of another mammal, the vehicle liquid is applied either on the target
skin area or on the
sheet, and the sheet is then applied on the target skin area, so that the
vehicle liquid is
between the sheet and the skin. Once the vehicle liquid is in contact with the
sheet and the
skin, the local anesthetic impregnated in the sheet begins to dissolve into
the vehicle liquid
and is delivered into the skin via the vehicle liquid. The sheet is
constructed to have a low
enough MVTR to keep the water in the vehicle liquid between the sheet and the
skin for a
time sufficient to deliver the needed amount of drug. The system is maintained
in place for a
time sufficient, for example 30 minutes, to deliver a sufficient amount of the
local anesthetic
agent to anesthetize the skin or to achieve a certain analgesic or anesthetic
effect. An
adhesion agent can be incorporated in the vehicle liquid to enable the vehicle
liquid to serve
as a weak "glue" to keep the sheet properly adhered on the skin for the
duration of the
application period. The adhesion can be strong enough so that the sheet stays
on the skin even
if the patient moves or changes the position of the body part that contains
the skin area.
Alternatively, the adhesion agent can be impregnated in the sheet, and
dissolves into the
vehicle liquid when vehicle liquid is brought into contact with the sheet. The
vehicle liquid
can be applied on the target skin area or the sheet in several different ways,
including sprayed
on the skin or the sheet, brushed on the skin or the sheet; soaked in a sheet
of absorbent
material (to form a "wet sheet") which is then applied on the skin or the
sheet, or crosslinked
into a solidified hydrogel sheet which is then applied on the skin or the
sheet. Optionally, the
sheet can have a dry-ending MVTR so that it can keep the water in the vehicle
liquid under
the sheet long enough to deliver a sufficient amount of the drug into the skin
to achieve a
desired anesthetic or analgesic effect, but by the end of the application
period a sufficient
amount of water in the vehicle liquid under the sheet has evaporated through
the sheet so that
when the sheet is removed from the skin at the end of the application period,
the skin is
substantially free of liquid so that the need to wipe off the residual liquid
on the skin is
avoided.
[0042] The dry-ending MVTR can be achieved in several ways: (1) Selecting a
film or tape
such as a MVTR control layer or barrier film with the appropriate MVTR and
laminating a
porous (very high MVTR) fabric onto it. The film or tape determines the MVTR
for the
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overall sheet, and the drug or excipients can be impregnated into the fabric
layer. For
example, a polyurethane film or tape or a microporous film or tape with an
appropriate
MVTR can be used for this purpose. (2) Using a film that has the proper MVTR
and is
capable of accommodating the drug (optionally with the help of a fastening
agent). A
polyurethane film, microporous polyethylene or rayon film or tape may be used
for this
purpose. Similarly, a layer of foam sponge with the proper MVTR may also be
used in this
approach. (3) Dispensing a solution comprising a film-forming substance onto a
layer of
fabric material with very high MVTR, evaporate off the solvent and form a film
on the fabric.
If the film-forming substance and its quantity dispensed on the fabric sheet
are selected
properly, a film with the MVTR in the desired range can be formed. Optionally,
the film-
forming substance is not readily soluble in the vehicle liquid so that it is
not easily destroyed
during the application.. In some embodiments of the current invention, the
film-forming
substance can also play the role of fastening agent. The ideal value of dry-
ending MVTR for
a particular system is dependent on factors such as the quantity and the
composition of the
vehicle liquid placed between the sheet and the skin, the length of the
designed drug delivery
period, and the conditions of the skin. Therefore, different systems with
different applications
can require different dry-ending MVTRs. In some embodiments, the dry-ending
MVTR of
the sheet is in the range of 100 to 10,000 gramim2/24 hours. In some other
embodiments,
ending-dry MVTR of the sheet is in the range of 200 to 6,000 gram/m2/24 hours.
[0043] In some embodiments of the current invention, the vehicle liquid
comprises a
crosslinkable but uncrosslinked polymer and the sheet comprises a crosslinking
agent capable
of crosslinking the crosslinkable polymer in said vehicle liquid. When the
vehicle liquid and
the sheet are brought into contact, the crosslinking agent in the sheet
diffuses into the vehicle
liquid and crosslinks the polymer, which solidifies the vehicle liquid. When
the sheet is
removed from the skin after the application period, the solidified vehicle
liquid, which is
adhered to the sheet, is lifted with the sheet. No or very minimal residue is
left on the skin.
[0044] The vehicle liquid can have an appropriate viscosity for facilitating
the application on
the skin or the sheet and the delivery of the drug into the skin. For vehicle
liquid that is
spread on the skin with a brush or a spatula or a Q-tip, if the viscosity is
too low, maintaining
an appropriate quantity of the vehicle liquid on the skin before the sheet is
applied can be
difficult because a low viscosity liquid can flow away from the target skin
area easily. If the
viscosity is too high, the application of it on the target skin area can be
difficult. The vehicle
liquid that is to be spread on the skin (as opposed to spayed on the skin) can
have a viscosity
in the range of 100 to 1 million centipoises, alternatively in the range of
500 to 200,000
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centipoise, and alternatively in the range of 1,500 to 50,000 centipoise.
However, in systems
in which the vehicle liquid is to be sprayed on the sheet or skin, the
viscosity of the vehicle
liquid is preferably lower, and can be as low as that of water or lower.
[00451 The sheet can be optionally stretchable (elastic) so that it can better
maintain intimate
contact with the skin area if the skin area is stretched when the patient
moves. It is desirable
that the sheet can be stretched to increase its length by at least 5% in at
least one direction
=
without breaking.
[0046] The drug can be impregnated in the sheet with the help of a "fastening
agent". For
example, tetracaine and poly vinyl alcohol (PVA) can be dissolved in an
isopropyl alcohol:
water solution (e.g. 50:50 by weight), which is then evenly dispensed into the
absorbent
fabric part of a sheet. After evaporating off the isopropyl alcohol and water,
the PVA solid
binds with both the fabric and the tetracaine, thus "fastens" the tetracaine
on the sheet.
[0047] In another embodiment, a system for delivering tetracaine into human
(or other
mammalian) skin comprises a first component and a second component. The first
component
comprises a sheet of a solid and flexible material and is impregnated with
tetracaine base, and
optionally a fastening agent or optionally an adhesion agent. A single
substance may serve as
both the fastening agent and the adhesion agent. The sheet is free of water so
the tetracaine
impregnated in it is not subject to significant hydrolytic degradation before
it is brought into
contact with the vehicle liquid. The second component is a vehicle liquid
comprising water
and optionally an adhesion agent. The two components are stored separately. To
use the
system to deliver the tetracaine into human (or other mammalian) skin, the
vehicle liquid is
applied either on the target skin area or on the sheet, and the sheet is then
applied on the
target skin area, so that the vehicle liquid is between the sheet and the
skin. Once the vehicle
liquid is in contact with the sheet and the skin, tetracaine impregnated in
the sheet begins to
dissolve into the vehicle liquid and is delivered into the skin via the
vehicle liquid. The sheet
has a sufficiently low MVTR to keep an appropriate amount of the vehicle
liquid between the
sheet and the skin for a period of time sufficient to deliver an amount of
tetracaine to achieve
the desired anesthetic or analgesic effect (this MVTR is referred to as
"sufficiently low
MVTR for tetracaine delivery"). Sufficiently low MVTR for tetracaine delivery
can depend
on factors such as quantity of the vehicle liquid applied between the skin and
the sheet as
well as skin and ambient temperatures, and can mean MVTR values lower than
5,000
g/m2/24 hours. In certain embodiments, the MVTR of the sheet is in the range
of 200 to
10,000 g/m2/24 hours. In other embodiments, the MVTR of the sheet is in the
range of 600
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to 6,000 g/m2/24 hours. The sheet has an MVTR control layer which is typically
a barrier
film or tape.
[0048] Optionally, the sheet also has the later diffusion function or has a
later diffusion layer.
The sheet can be a laminated sheet comprising a fabric layer and a barrier
film, laminated
together with adhesive or with heat. In its application, the system is kept on
the skin for
sufficient time to deliver a sufficient amount of tetracaine for the desired
application. In some
of these embodiments, the amount of tetracaine in each cm2 of the sheet can be
at least 0.1
mg. In others, the amount of tetracaine in each cm2 of the sheet can be at
least 0.15 mg or at
least 0.3 mg. In other such embodiments, the amount of tetracaine in each cm2
of the sheet
can be between 0.5 mg and 3 mg, or between 1 and 2 mg. Tetracaine quantities
higher than 3
mg/cm2 will also work, but may be unnecessary. Therefore, in some of the
embodiments, the
average tetracaine quantity per unit sheet area (total tetracaine quantity
divided by area of the
sheet) is no more than about 3 mg/cm2. The desired length of the application
time can be
dependent on the application. For example, with a properly made and used
system (i.e.
appropriate amount of tetracaine per cm2, low enough sheet MVTR so that the
skin under the
sheet is kept wet for at least 30 minutes, appropriately formulated vehicle
liquid, and an
appropriate quantity of the vehicle liquid between the skin and the sheet),
such as that in
Example 1, normal human skin in normal ambient conditions can be anesthetized
within 240
minutes, within 120 minutes, within 60 minutes, or even within 45 minutes. In
these
embodiments, tetracaine is not subject to significant hydrolytic degradation
during storage
since the sheet is free of water, thus providing a long shelf life. When
tetracaine dissolves
into the vehicle liquid after the sheet and the vehicle liquid are brought
into contact with each
other, the tetracaine becomes subject to hydrolytic degradation. However,
since the
application time is usually not longer than a few hours, tetracaine loss due
to the hydrolytic
degradation during the application period is minimal and is of no practical
significance. The
amount of the vehicle liquid applied between the skin and the sheet is
preferably
approximated to be in the range of from about 2 to about 200 mg/cm2, or in the
range of from
about 10 to about 50 mg/cm2.
[0049] Tetracaine in solutions with a low pH, such as 6.0 or lower, including
5.5 or lower,
can have slow enough hydrolytic degradation rates to have a decent shelf life
(e.g. 1-2 years)
in room temperature storage. However, the pH of the vehicle solution has to be
higher than
about 6.5, including higher than about 7.5, to deliver tetracaine into intact
human skin to
achieve skin anesthesia within 60 minutes. For avoiding these conflicting pH
requirements
for stability and high delivery rates, a system in another embodiment of the
current invention
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for delivering tetracaine into human skin comprises a first component and a
second
component. The first component comprises a sheet of a solid and flexible
material and is
impregnated with a pH modifying agent which is capable of increasing the pH of
the vehicle
solution when dissolved in it. The second component is a vehicle liquid
comprising water,
tetracaine, and having a pH lower than about 6.0, and the tetracaine
degradation loss in the
vehicle solution is less than 8% per year at room temperature, preferably less
than 4% per
year at room temperature. To use the system to deliver tetracaine into human
skin, the vehicle
liquid containing tetracaine is applied either on the target skin area or on
the sheet, and the
sheet is then applied on the target skin area so that the vehicle liquid is
between the sheet and
the skin. After the vehicle liquid is in contact with the sheet and the skin,
the pH modifying
agent impregnated in the sheet dissolves into the vehicle liquid and increases
the pH of the
vehicle liquid to higher than about 6.5, including higher than about 7.5. This
pH increase
converts many tetracaine molecules from the ionized state (associated with low
skin
permeability) to unionized state (associated with higher skin permeability),
thus increasing
the tetracaine delivery rates into the skin. The system is kept on the skin
for sufficient time to
deliver a sufficient amount of tetracaine for the desired application. The
concentration of
tetracaine in the vehicle solution, optionally in the form of tetracaine
hydrochloride, can be
from about 0.1% to about 20%, and, in certain embodiments, from about 0.4% to
about 6%.
Many bases or buffers can be used as the pH modifying agent, including sodium
bicarbonate,
phosphate buffer, and sodium borate.
[0050] In another embodiment, a system for delivering tetracaine into human
skin comprises
a first component and a second component. The first component comprises a
sheet of a solid
and flexible material and is impregnated with a tetracaine salt, such as
tetracainc
hydrochloride, and optionally a fastening agent or optionally an adhesion
agent. The second
component is a vehicle liquid comprising water and pH-modifying agent (the
function of
which is described in detail below), and optionally an adhesion agent. To use
the system to
deliver the tetracaine into human skin, the vehicle liquid is applied either
on the target skin
area or to the sheet, and the sheet is then applied on the target skin area,
so that the vehicle
liquid is between the sheet and the skin. Once the vehicle liquid is in
contact with the sheet
and the skin, the tetracaine salt impregnated in the sheet begins to dissolve
into the vehicle
liquid. The pH modifying agent in the vehicle liquid coverts many of the
dissolved tetracaine
molecules from the ionized species to unionized species which permeate into
the skin at a
higher rate since the unionized species has better skin permeability than the
ionized species.
The sheet is selected to have an MVTR such that the vehicle liquid applied
between the sheet
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and the skin is kept there for a long enough time to deliver a sufficient
amount of tetracaine to
achieve the desired effect. The sheet has an MVTR layer which is typically a
barrier film or
tape. Optionally, the sheet also has a lateral diffusion function or has a
lateral diffusion layer.
The system is kept on the skin for sufficient time to deliver a sufficient
amount of tetracaine
for the desired application.
[0051] In some of these embodiments, the amount of tetracaine salt in each cm2
of the sheet
can be at least 0.1 mg. In others, the amount of tetracaine in each cm2 of the
sheet can be at
least 0.15 mg or at least 0.3 mg. In yet others, the amount of tetracaine salt
in each cm2 of the
sheet can be between about 0.5 mg and about 3 mg, or between about 1 to about
2 mg. The
desired length of the application time can be dependent on the application.
For example, with
a properly made system (i.e. containing an appropriate amount of tetracaine
salt per cm2 and
having a low enough sheet MVTR such that the skin under the sheet is kept wet
for at least
30 minutes, and using an appropriately formulated vehicle liquid, with an
appropriate
quantity of the vehicle liquid between the skin and the sheet, on normal human
skin in normal
ambient conditions, can be anesthetized within 240 minutes, within 120
minutes, within 60
minutes, or even within 45 minutes.
[0052] Other embodiments of the current invention are related to a system
comprising water
and an MVTR control layer such as a barrier film (a film whose MVTR is lower
than
5,000/m2/24 hour) and tetracaine, wherein said tetracaine is distributed co-
extensively with
said barrier film (either in the barrier film or in another layer of material
co-extensive with
the barrier film), and wherein said water is brought into contact with said
tetracaine within
one hour of application of said system on a mammal's skin.
[0053] In another embodiment, methods of using some of the aforementioned two-
component drug delivery systems for producing anesthesia in human or other
mammalian
skin, including tissues under the skin, prior to painful procedures are
provided. As described
previously, in some of the embodiments, the first component of the system
comprises a sheet
of a solid and flexible material, and the second component comprises a vehicle
liquid. A local
anesthetic (such as tetracaine) is impregnated in the sheet, and the vehicle
liquid comprises
water. A fastening agent can be optionally impregnated in the sheet to fasten
the tetracaine
(or other local anesthetic) to the sheet. An adhesion agent can be impregnated
in the sheet or
incorporated in the vehicle liquid. The sheet and the vehicle liquid are
stored separately. To
use the system for producing the anesthesia, the vehicle liquid is applied
either on the target
skin area or on the sheet, and the sheet is then applied on the target skin
area, so that the
vehicle liquid is between the sheet and the skin. Once the vehicle liquid is
in contact with the
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sheet and the skin, the local anesthetic impregnated in the sheet begins to
dissolve into the
vehicle liquid and is delivered into the skin via the vehicle liquid. The
system is kept on the
skin for sufficient time to deliver a sufficient amount of the local
anesthetic agent to produce
adequate anesthesia in the tissues. The "sufficient time" depends on factors
such as the
composition of the vehicle liquid, the MVTR of the sheet, the individual's
skin permeability
to the local anesthetic agent, the depth of the tissue to be anesthetized, and
how painful the
procedure is (if there is no anesthesia). The "sufficient time" can be as
short as 15 minutes,
especially for human facial skin or mucosa, but may be 30, 45, or 60 minutes.
In situations
where the procedure is particularly painful, such as laser tattoo removal or
some biopsy
procedures, the sufficient time may be as long as 120 minutes. It is also
possible that the skin
is not anesthetized after a relatively short application time, such as 15 to
30 minutes, but
becomes anesthetized some time (e.g. 30 minutes) after the system is removed
from the skin
(see some Examples below). That is because some quantities of tetracaine can
be stored in or
under the stratum corneum layer during the application period and continue to
penetrate
deeper after the application period. Examples of painful procedures include,
but are not
limited to, needle injections; laser procedures such as laser tattoo removal,
laser spider vein
removal, laser hair removal, laser skin resurfacing; and the application of
capsaicin-
containing formulations on skin, botox or filler injections.
[00541 In another embodiment, a method of using some of the aforementioned two-
component drug delivery systems for reducing the pain associated with herpes
zoster in the
pre-eruptive phase (preherpetic neuralgia), acute eruptive phase, or chronic
phase
(postherpetic neuralgia), is provided. As described previously, in some of the
embodiments,
the first component of the system comprises a sheet of a solid and flexible
material, and the
second component comprises a vehicle liquid. A local anesthetic (such as
tetracaine) is
impregnated in the sheet. The vehicle liquid comprises water. A fastening
agent can be
optionally impregnated in the sheet to fasten the tetracaine (or other local
anesthetic) to the
sheet. An adhesion agent can be impregnated in the sheet or incorporated in
the vehicle
liquid. The sheet and the vehicle liquid are stored separately. To use the
system, the vehicle
liquid is applied either on the skin area suffering from the pain or on the
sheet, and the sheet
is then applied on the skin area suffering from the pain, so that the vehicle
liquid is between
the sheet and the skin. When the vehicle liquid is in contact with the sheet
and the skin, the
local anesthetic impregnated in the sheet dissolves into the vehicle liquid
and is delivered into
the skin via the vehicle liquid. The system is kept on the skin for sufficient
time to
significantly reduce the pain. With an appropriately formulated system and
method of using
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it, the pain can be significantly reduced within 60 minutes of the
application. If the herpes
zoster is in its acute (eruptive) phase and the stratum comeum layer of the
skin (the main
barrier of the skin) is broken, pain reduction can be achieved even sooner. If
the skin is
broken, has blisters or rash (significantly compromised or missing the stratum
comeum) in
the acute eruptive phase of a herpes zoster infection, the time to achieve
significant pain
reduction can be much shorter than if the skin has intact stratum comeum. In
those cases it
may be possible to achieve significant pain reduction within a few minutes
following the
application of the system. However, maintaining the system on the lesion for
longer time,
such as between 5 and 60 minutes, can be more beneficial because that allows
more
tetracaine to be delivered into the tissues under the sheet, especially fatty
tissues that can
store tetracaine, and result in a longer lasting pain reduction effect. If the
skin is broken and
sufficient amount of bodily fluid is oozing out of the lesion, the sheet may
be applied directly
to the lesion without the vehicle fluid, as the bodily fluid may work as the
vehicle liquid.
Tetracaine is an exemplary drug in this embodiment because it produces a
longer analgesic
effect after the drug formulation is removed from the skin than other commonly
used
anesthetics such as lidocaine and prilocaine. This long "tail" of analgesic
effect after the drug
delivery system is removed from the skin is particularly desirable for
treating herpes zoster in
its acute eruptive phase, because after applying the system on the diseased
skin for as short as
one hour, the skin can continue to enjoy pain reduction for many hours. This
allows the skin
to be treated by other topical medications. When tetracaine is used as the
drug, the system is
also desirable for reducing pain associated with herpes zoster in the chronic
phase, also
known as post herpetic neuralgia. That is because an application of the system
for as short a
time as one hour can produce significant pain reduction for many hours, for
example 5-12
hours. The skin area is thus not covered with the treatment formulation or
structure for most
of the day, which minimizes occlusion-induced skin irritation and discomfort
or interference
with the patient's daily activities such as exercise, work, shower, and sleep.
For example, the
patient can apply the system for one hour every 6-12 hours and get significant
pain reduction
or even elimination around the clock. Because pain associated with post
hetpetic neuralgia
can last months to years, the short application time coupled with long lasting
pain reduction
associated with a system comprising tetracaine can mean a significantly
reduced skin
irritation and discomfort, which may in turn provide a better quality of life
for patients, when
compared with other treatment options.
[0055] In another embodiment, a method of using some of the aforementioned two-
component drug delivery systems for reducing neuropathic pain is provided. As
described
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previously, in some of the embodiments, the first component of the system
comprises a sheet
of a solid and flexible material, and the second component comprises a vehicle
liquid. A local
anesthetic (such as tetracaine) is impregnated in the sheet, and the vehicle
liquid comprises
water. The sheet may also comprise a fastening or an adhesion agent. The
fastening agent
may also work as the adhesion agent. The sheet and the vehicle liquid are
stored separately.
To use the system, the vehicle liquid is applied either on the target skin
area or to the sheet,
and the sheet is then applied on the target skin area, so that the vehicle
liquid is between the
sheet and the skin. When the vehicle liquid is in contact with the sheet and
the skin, the local
anesthetic impregnated in the sheet dissolves into the vehicle liquid and is
delivered into the
skin via the vehicle liquid. The system is kept on the skin for sufficient
time to significantly
reduce the pain. Neuropathic pain includes but is not limited to pain
associated with zoster,
diabetes-related nerve damage, neuroma (tumor-induced or trauma-induced);
nerve damages
caused by viral diseases; nerve compression or pinch, and pain or headache
associated with
occipital neuralgia.
[0056] In another embodiment, a method of using some of the aforementioned two-
component drug delivery systems for reducing musculoskeletal pain is provided.
As
described previously, in some of the embodiments, the first component of the
system
comprises a sheet of a solid and flexible material, and the second component
comprises a
vehicle liquid. A local anesthetic (such as tetracaine or lidocaine) is
impregnated in the sheet,
and the vehicle liquid comprises water. The sheet may also comprise a
fastening or an
adhesion agent. The fastening agent may also work as the adhesion agent. The
sheet and the
vehicle liquid are stored separately. To use the system, the vehicle liquid is
applied either to
the sheet or to the target skin area, and the sheet is then applied to the
skin area, so that the
vehicle liquid is between the sheet and the liquid. When the vehicle liquid is
in contact with
the sheet and the skin, the local anesthetic impregnated in the sheet
dissolves into the vehicle
liquid and is delivered into the skin via the vehicle liquid. The system is
kept on the skin for a
pre-determined period of time before being removed. This process may be
repeated once or
multiple times a day for days or weeks. Musculoskeletal pain includes but is
not limited to
pain associated with osteoarthritis; rheumatoid arthritis; myofacial pain;
carpal tunnel
syndrome; complex regional pain syndrome; tennis elbow; soft tissue and bone
injuries such
as a sprained ankle, knee, shoulder, wrist, elbow, back; and spondylitis.
Musculoskeletal
pain also includes pain in bones and joints with any or unknown cause, such as
neck, knee,
spine, or back pain with any or unknown cause. In treating musculoskeletal
pain with the
system, significant pain reduction may or may not be achievable with a single
application of
1r1
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the system. It is possible that multiple applications over a period of hours,
days, or even
weeks, are needed before significant pain reduction can be achieved. In those
cases, the
length of each application may not necessarily be designed to be long enough
to produce
instantaneous pain reduction, but to deliver sufficient amount of the drug
each time (e.g., at
least 30 minutes, 30 minutes, 60 minutes; or 2 hours for tetracaine; 2-12
hours for other local
anesthetics) so that significant pain reduction is achieved after several
applications. In some
cases, the system is such that the tetracaine impregnated in said sheet has a
sufficient quantity
per cm2 and a sufficient dissolution speed into the appropriate quantity of
said vehicle liquid
placed between said sheet and a normal human skin area to be able produce
anesthesia in said
normal human skin within 120 minutes, or even within 60 minutes, under normal
ambient
conditions. Although the purpose of these treatments is to reduce
musculoskeletal pain
instead of to produce skin anesthesia, the time it takes to produce skin
anesthesia is a measure
of the tetracaine's dermal permeation rates and can be used to gauge the speed
of tetracaine
delivery or the quantity of tetracaine delivered.
[0057] After one application of the tetracaine delivery systems of the current
invention,
sufficient amount of tetracaine may still exist in the sheet for another
application to achieve a
desired anesthetic or analgesic effect. Therefore, one of the embodiments of
the current
invention provides a method of using the sheet and liquid combination system
comprising
tetracaine for obtaining an anesthetic or analgesic effect, as described in
many places in the
current application, except the user uses the sheet one or more times.
[00581 Although the systems of the current invention that comprise a local
anesthetic, such as
tetracaine, are capable of producing anesthetic or analgesic effects in intact
skin or tissues
close to intact skin surface, they can also be used to treat pain in
compromised skin, such as
scalded skin or mucosal tissues. If the skin area's stratum corneum layer is
completely
destroyed, such as badly scalded or burned skin, the two-component systems
comprising a
local anesthetic, as described above, can provide longer-lasting pain relief
with a lower risk
of local anesthetic overdose than simply applying a local anesthetic solution
(e.g. 1%
lidocaine hydrochloride solution) onto the wounded skin. That is because the
local anesthetic
in a typical solution, in which the local anesthetic is completely dissolved,
can be quickly
absorbed by the capillary blood vessels in the wound that are directly exposed
to the solution,
while the local anesthetic in the system of the current invention has to
dissolve from the sheet
and into the vehicle solution or the bodily fluid oozing out of the wound,
which takes time.
To further extend the drug release time from the sheet and reduce the over
exposure risk, the
local anesthetic can be incorporated in an ion-exchange resin to form a local
anesthetic-ion
nn
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exchange resin complex which is impregnated in the sheet. When applied on the
wounded
skin, the local anesthetic molecules can only be exchanged out of the complex
by ions in the
bodily fluid or the vehicle solution, one ion for each local anesthetic
molecule. Because the
bodily fluid or the vehicle liquid has limited supply of ions, and
replenishing the ions used in
exchanging out the local anesthetic molecules takes time, the release rate of
the local
anesthetic from the sheet is more even over time and the delivery of the local
anesthetic into
the wounded skin is more sustained over time. Such a system can be
beneficially used to treat
pain in situations such as burns or deep scalding wounds, or trauma caused by
accidents or
war acts.
[0059] In some of the applications using the embodiments of the current
invention, such as
aforementioned treatment of musculoskeletal pain and neuropathic pain, the
systems of the
current invention may be used with localized heat for achieving deeper
penetration of the
drug into the tissues. For instance, a tetracaine-impregnated sheet, such as
one described in
some of the Examples below, can be applied over the knee of a patient
suffering from pain
associated with arthritis, with the vehicle liquid placed between the sheet
and the knee skin.
A heat generating device, such as a ThermaCare brand air-activated heatwrap,
can be placed
over the sheet already on the knee. The local heat can increase the skin
temperature and likely
make the tetracaine penetrate deeper into the knee tissues, which may mean
better pain relief.
100601 In another embodiment, a method for reducing pain associated with sores
in the oral
cavity is provided. The system comprises the first component of a sheet of a
solid and
flexible material, and the second component is the saliva of the patient. A
local anesthetic
such as tetracaine or lidocaine is impregnated in the sheet. The sheet may
also comprise a
barrier film, a fastening agent, and/or an adhesion agent. The fastening agent
may also work
as the adhesion agent. To use the system, the sheet is applied over the sore
area in the oral
cavity. The saliva naturally present on the sore surface serves the vehicle
liquid. The local
anesthetic impregnated in the sheet dissolves into the saliva between the sore
surface and the
sheet and is delivered into the sore tissue. The pain associated with the sore
can be
significantly reduced within a few minutes.
[0061] In general, the systems of the current invention separate elements of a
dermal drug
delivery system into two or more components to avoid incompatibility or to
gain other
benefits, and provide methods for the components to be joined prior to or
during the drug
delivery application to deliver the drug at sufficient rates to achieve the
desired clinical
effect. The term "incompatibility" in the current invention means when the
elements are
incorporated in one formulation or are in contact with each other in another
way during
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storage, at least one of them or the formulation itself becomes chemically or
physically
unstable to the point that a shelf life of at least one year cannot be
achieved at room
temperature (based on US FDA standards).
100621 In some embodiments of the current invention, the rationale behind
storing the sheet
and fluid separately and combining them shortly before or at the application
is not to avoid
incompatibility, but to gain other benefits. In some such embodiments, a local
anesthetic (e.g.
lidocaine or tetracaine) is impregnated into a polyurethane film by soaking
the film in a local
anesthetic solution (see Example 38). When this film is applied to a wound
surface, the local
anesthetic in the film diffuses into the bodily fluid on the wound surface and
then into the
wound tissue, reducing the pain associated with the wound. In this system, the
bodily fluid of
the wound surface is used as the "liquid" part of the sheet and liquid
combination system.
Additional fluid, such as water, may also be used if more fluid is desirable.
The advantages of
this system include sustained local anesthetic release into the wound without
quick absorption
of the drug into systemic circulation, which would happen if a local
anesthetic solution is
simply applied to the wound surface, due to the open capillary blood vessels
in the wound
which quickly absorb the drug into systemic circulation. Further advantages
include
protection of the wound surface from infectious substances and breathability
provided by the
breathable nature of the polyurethane film. Drugs other than local
anesthetics, such as anti-
infection agents including, but not limited to, chlorhexidine, can also be
impregnated into the
film and be used to treat the wound.
[00631 In treating musculoskeletal pain in a joint with the sheet and liquid
combination
system of the current invention, the sheet applied on the joint may need
support (in addition
to the adhesive agent) to stay adhered to the skin. The joint's movement may
have the
tendency to cause the sheet and the skin to separate. Therefore, in some of
the embodiments
of the current invention, the sheet, after being applied to the skin with the
vehicle liquid, is
wrapped with a wrapper to help keep the sheet in contact with the skin. It is
desirable that
such a wrapper is made of a breathable material, such as, without limitation,
an elastic fabric
material (i.e. Ace bandage), whose MVTR is much higher than that of the sheet
(such as
MVTR higher than 10,000 g/m2/24 hour). In this way, the dry-ending MVTR
feature of the
sheet may be maintained.
[00641 Some embodiments of the current invention are related to a sheet for
delivering
tetracaine into human skin, comprising at least 0.1 mg tetracaine/cm2, wherein
said sheet is
free of water and said sheet's MVTR is lower than 5,000 g/m2/24 hours, and
preferably lower
than 2,000 g/m2/24 hours, and can be in the range of between 200 and 10,000
gram/m2/24
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hours, 600 to 6,000 gram/m2/24 hours, or 200 to 2,000 gram/m2/24 hours. This
sheet can
further comprise a lateral diffusion layer which can be a layer of fabric
material, such as
woven gauze, non-woven absorbent fabric material, paper, open-cell foam, and
cloth. The
sheet's MVTR property can be provided by a barrier film, such as polyurethane
film. The
barrier film and the fabric material layer can be laminated together with heat
or adhesive. The
sheet can also comprise a fastening agent for fastening the active drug and
other ingredients
onto the sheet. The sheet can further comprise an adhesion agent (such as poly
vinyl alcohol)
for facilitating the adhering of the sheet, when combined with a vehicle
liquid, on to the
target skin area. When such a sheet is applied on normal human skin alone or
without a
vehicle liquid comprising water, it cannot produce anesthesia in said normal
human skin
within 120 minutes under normal ambient conditions. However, when such a sheet
is applied
on normal human skin with 25 mg water/cm2 between said sheet and said skin, it
can produce
anesthesia in said normal human skin within 120 minutes under normal ambient
conditions.
The sheet may further comprise a vasoconstriction agent such as one selected
from the group
of lidocaine, ephedrine, epinephrine, oxymetazolin, tetrahydrozoline,
xylometazoline,
phenulphrine, tyramine, naphazoline, caffeine, isoprenaline, pseudoephedrine,
orciprenaline,
salbutamol, terbutaline.
[0065] The sheet and liquid combination systems of the current invention for
delivering
tetracaine or other local anesthetic into the skin can also include a
vasoconstriction agent. A
vasoconstriction agent delivered into the skin along with the local anesthetic
can reduce the
blood flow in the skin area and reduce the speed of clearance of the local
anesthetic agent
from the skin. As a result, the analgesic or anesthetic effect will last
longer. This is an
important advantage for pain control applications, because it can potentially
reduce the
frequency of application which is more convenient to patients and more cost
effective.
Vasoconstriction agents are molecules capable of constricting the blood
vessels, as
commonly known in the medical community. They include, without limitation,
lidocaine,
ephedrine, epinephrine, oxymetazolin, tetrahydrozoline, xylometazoline,
phenulphrine,
tyramine, naphazoline, caffeine, isoprenaline, pseudoephedrine, orciprenaline,
salbutamol,
and terbutaline.
[0066] In some of the aforementioned applications, only the systems in which
the local
anesthetic is impregnated in the sheet is used in illustrating how some of the
embodiments
can be used in the medical applications. However, that is only for example
purposes. Other
aforementioned systems (e.g. the active drug is in the vehicle liquid) may
also be used for the
same purposes.
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[0067] The current invention is also related to a novel manufacturing method
of a flexible
sheet impregnated with a drug. In typical manufacturing of drug-in-adhesive
patches, a thin
layer of a mixture of the drug, a pressure sensitive adhesive and volatile
solvent is cast onto a
backing film. Since the amount of the drug in the patch is proportional to the
thin cast layer's
thickness, the thickness must be precisely controlled, which can demand high
precision of the
machinery's design and operation. In the current invention, the preferred
manufacturing
method involves a different way to dispense the drug onto the sheet. The drug
and the
fastening agent are dissolved in a volatile solvent. The solution is then
dispensed onto the
sheet with a volume displacement method, for example with a multi-channel
pipette array in
which each of the pipettes in the array dispenses a pre-determined volume of
the solution by
volume displacement in each movement. For example, 300 pipettes can be
arranged to form
a 10 X 30 evenly-spaced rectangular array to cover a 10 cm X 30 cm area. With
each
movement of the volume displacement, each pipette dispenses 40 microliters of
the solution
onto the sheet, so that 12,000 microliters of the solution is dispensed on 300
cm2 of the sheet
with each movement of the volume displacement. The side of sheet receiving the
solution
preferably is a material very absorbent to the solution (lateral diffusion
layer), such as the
gauze side of a gauze-tape laminate sheet. The dispensed solution can thus be
quickly
absorbed into the absorbent material and flows into even distribution within
said sheet of
absorbent material. For example, each of the 40 microliter drops of the
solution dispensed on
the sheet can flow laterally into surrounding areas, so that an even
distribution of the solution
will be on the sheet some time (e.g., within 30 seconds) after the 300 drops
of the solution are
dispensed on the sheet. The volatile solvent in the solution is then
evaporated off, preferably
by passing the sheet through a heating chamber, leaving only the drug and the
fastening agent
on the sheet. Because it is easier to achieve precise solution dispensing by
volume
displacement or weighing (in comparison with precisely controlling the
thickness of adhesive
cast layer in typical drug-in-adhesive patch manufacturing), the sheet can be
made at low
cost. The phrase "even distribution within said sheet of absorbent material"
and the like
means the distribution of the drug in the sheet is even enough that no area of
the sheet
contains no drug, or, if the drug is a local anesthetic, that the skin area
treated with the sheet
and proper vehicle liquid is relatively evenly anesthetized. "Even
distribution" does not
necessarily mean the drug quantity per unit area is exactly the same
everywhere in the sheet.
EXAMPLES
[0068] In many of the examples below, the ability of the system to numb human
skin is used
to gauge the effectiveness or stability of tetracaine-impregnated sheets. It
should be pointed
'IA
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out that this measurement was only used as a surrogate to measure the rate
and/or quantity of
delivery of tetracaine into the skin. The ultimate purpose of the sheets of
the current invention
that comprise tetracaine can be numbing the skin or other than numbing the
skin, such as
treating musculoskeletal pain, as mentioned previously.
Example 1
[0069] The following system for providing skin anesthesia or analgesia
comprising a sheet
and a vehicle liquid was made and used as an exemplary embodiment of the
current
invention.
[0070] (1) In this and other examples, tetracaine or TC means tetracaine base,
unless
specified otherwise. Tetracaine (base), USP (Spectrum Chemical) was dissolved
in an
isopropyl alcohol:water solution (70:30 by volume, rubbing alcohol, Western
Family brand)
to obtain a 10% tetracaine (by weight) solution. In this and other Examples,
"70% isopropyl
alcohol" or "70% isopropyl alcohol solution", or rubbing alcohol, means
Western Family
brand rubbing alcohol, which is 70% isopropyl alcohol, 30% water solution by
volume. (2) A
sheet of gauze (DuSoft brand Non-Woven Sponge, Dumex, No.84122, single ply)
was
placed on the adhesive side of a poly urethane tape (Tegaderm Tape,3M,
purchased from
Ortho-Med) to form a laminated sheet. (3) 0.72 gram of the 10% tetracaine
solution was
evenly dispensed onto 30 cm2 of the gauze side of the laminated sheet. The
solution was
absorbed into the gauze part of the sheet. The sheet was then placed in a
heating chamber
(temperature cycled in an approximate range of 40-50 C) for about 30 minutes
to let the
isopropyl alcohol and water completely evaporate. Each cm2 of the dried sheet
contained 2.4
mg tetracaine. (4) Separately, a vehicle liquid containing 0.5% Carbopol 981,
NF in water,
with the pH adjusted to about 7 with NaOH (approximately 0.23% NaOH), was
made. The
vehicle liquid was a clear, viscous but flowable solution.
[0071] To test the system's effect, a thin layer of the vehicle liquid was
applied with a thin
wood stick to a skin area of approximately 5 cm2 on a human subject's left
forearm. The
thickness of the vehicle liquid layer was such that it was barely thick enough
to form a
continuous layer. A piece of the tetracaine-containing sheet, approximately 3
cm2, was then
applied onto the vehicle liquid layer, with the gauze side in contact with the
vehicle liquid.
The sheet was gently massaged to ensure good contact. The vehicle liquid
provided enough
adhesion between the sheet and skin (mainly due to the presence of Carbopol
981 as the
adhesion agent) so that the sheet stayed on the skin for the entire 60 minute
test period. Sixty
minutes after the sheet was applied, the sheet was removed from the skin. The
skin area that
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was covered by the vehicle liquid and the sheet was anesthetized (deeply
numb). The skin
area was also dry when the sheet was removed, suggesting that all the water in
the vehicle
liquid had evaporated through the sheet.
[0072] In the above system, tetracaine was not subject to hydrolytic
degradation before it was
brought into contact with the vehicle liquid because it existed in the sheet
that contained no
water. The tetracaine-impregnated sheet can thus be stored at room temperature
and has a
shelf life of at least two years. When the sheet was applied on the vehicle
liquid layer which
was on the skin area, the tetracaine in the sheet dissolved into the vehicle
liquid which
delivered the tetracaine molecules into the skin. The vehicle liquid, after
dissolving the
tetracaine in the sheet, had a pH high enough to keep a sufficient portion of
the tetracaine
molecules unionized to facilitate the achievement of anesthesia within 60
minutes.
Unionized tetracaine molecules have better skin permeability than ionized
tetracaine
molecules.
[0073] Since the permeation of the tetracaine into the skin stops or slows
down greatly when
all the water is evaporated, the system in this embodiment has the safety
feature of not
delivering the drug or delivering the drug at much reduced rates after the
desired application
period is over.
Example 2
[0074] The following system for providing skin anesthesia or analgesia
comprising a sheet
and a vehicle liquid was made and used as an exemplary embodiment of the
current
invention.
[0075] Step 1. Ten gram polyvinyl alcohol (PVA, sample from Amresco, molecular
weight
30,000 to 50,000) was placed in 90 gram distilled water and heated to
approximately 70 C
with periodical stirring until a homogeneous solution was obtained, yielding a
10% PVA (by
weight) solution.
[0076] Step 2. Five gram of the 10% PVA solution made in Step I was added to 6
gram
rubbing alcohol. The mixture was shaken until a homogeneous solution was
obtained.
[0077] Step 3. 0.58 gram tetracaine base, USP (Spectrum Chemical) was added
into the
solution made in Step 2. The solution was shaken until all tetracaine
particles were dissolved,
yielding a 5% tetracaine, 4.3% PVA solution (by weight).
[0078] Step 4. A gauze sheet (Dusoft Non-woven Sponges, No. 84148, single ply)
was
horizontally suspended on a lid-less box, so that the sheet was parallel to
the ground and the
solution-loading area of the gauze sheet was not in touch with any objects.
Approximate 4.5
0-14
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gram (about 5 mL) of the solution made in Step 3 was evenly dispensed onto the
125 cm2 the
solution-loading area of the gauze sheet with a 5 mL syringe. The sheet was
placed in an
oven with approximate 50-60 C temperature for 30 minutes to evaporate off the
water and
isopropyl alcohol, yielding a gauze sheet impregnated with approximate 1.8 mg
tetracaine
and 1.5 mg PVA per cm2.
[0079] Step 5. The gauze sheet made in Step 4 was laminated onto a poly
urethane tape
(Tegaderm Tape, 3M) using the tape's adhesive. The tetracaine and PVA
impregnated sheet
was thus completed.
[0080] Step 6. A vehicle liquid solution with the following ingredients was
made: 5%
glycerin, 7% polyvinylpyrrolidone, 0.1% carbopol 981, NF, 0.05% sodium
hydroxide,
87.85% distilled water.
[0081] The following experiment was performed to test the system made above.
[0082] Step 7. A layer of the vehicle liquid made in Step 6 was spread on a
human subject's
left forearm skin to cover a 3 X 4 cm area. The thickness of the layer was
such that the layer
was barely continuous (about 0.2 mm thick).
[0083] Step 8. The laminated sheet made in Step 5 (approximate 2 x 3 cm) was
placed on top
of the vehicle liquid layer, with the gauze side in touch with the vehicle
liquid. A Kleenex
tissue was used to tap on the sheet and surrounding area to ensure intimate
contact and
remove excess vehicle liquid outside the sheet area.
[0084] Step 9. Forty five minutes after the commencement of the application,
1/3 of the sheet
was lifted and the skin under it was scratched with the end of a straightened
paper clip. The
skin was anesthetized (deeply numb). The sheet was left on the skin until 120
minutes from
the commencement of the application before it was removed. The sheet adhered
to the skin
very well for the entire 120-minute test period even with movements of the
forearm. The skin
was still deeply numb when the sheet was removed.
Example 3
[0085] Step 1. Twenty five grams of polyvinyl alcohol (PVA, sample from
Amresco,
molecular weight 30,000 to 50,000) was placed in 75 grams distilled water and
heated to
approximately 70 C with periodical stirring until a homogeneous solution was
obtained,
yielding a 25% PVA (by weight) solution. This solution is referred to
hereafter as "25% PVA
solution".
[0086] Step 2. Three and two-tenths grams of the 25% PVA solution made in Step
1 was
added to 7.02 grams rubbing alcohol, 0.98 grams distilled water, and 0.8 grams
tetracaine
0,1
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base. The mixture was shaken until a homogeneous and clear solution was
obtained, yielding
a solution with 6.67% tetracaine and 6.67% PVA (by weight).
[0087] Step 3. A gauze sheet (Dusoft Non-woven Sponges, No. 84148, single ply)
was
laminated onto a sheet of the 3M 9832 polyurethane tape using the tape's
adhesive (the tape's
back release liner was still un-removed).
[0088] Step 4. About 5 mL of the solution (about 4.7 grams) made in Step 2 was
evenly
dispensed onto the gauze side of the sheet (about 160 cm2) made in Step 3 with
a 5 mL
syringe. The sheet was placed in an oven with approximate 50-60 C temperature
for 30
minutes to evaporate off the water and isopropyl alcohol, yielding a sheet
impregnated with
approximate 2 mg tetracaine and 2 mg PVA per cm2.
[0089] Step 5. Separately, a vehicle liquid solution with the following
ingredients was made:
0.05% Cabopol 981, N.F., 0.024% sodium hydroxide, 99.926% distilled water.
[0090] The following experiments were performed to test the system made above.
[0091] Step 6. The vehicle liquid of Step 5 was placed into a spray bottle and
sprayed on a
human subject's left forearm skin. The skin area was covered with densely
populated fine
beads of the vehicle liquid.
[0092] Step 7. A piece of the laminated sheet made in Step 4 (approximate 2 x
3 cm) was
placed on top of the vehicle liquid already on the skin area, with the gauze
side in touch with
the vehicle liquid. A Kleenex tissue was used to tap on the sheet and
surrounding area to
ensure intimate contact and remove excess vehicle liquid outside the sheet
area. Forty-five
minutes after the commencement of the application, the sheet was lifted and
the skin under it
was scratched with the end of a straightened paper clip. The skin was deeply
numb. The sheet
stayed on the skin despite the skin being moved and stretched during the 45
minutes.
Although the sheet wrinkled a little bit during the 45 min wear time due to
the movement of
the arm skin, all the skin area under the sheet was deeply numb, suggesting
that slight
separation between the sheet and the skin did not affect the anesthesia
effect. That may be
because at places where the sheet "wrinkles" (i.e., separates from the skin),
the vehicle liquid
was still on the skin. Enough tetracaine could have dissolved into the vehicle
liquid in the
first several minutes of the application (before the wrinkles were formed), so
that enough
tetracaine was delivered into the skin to numb the skin even at places where
the sheet
wrinkled.
[0093] Step 8. In a separate test, a layer of another vehicle liquid (1.6%
Carbopol 981, 0.9%
sodium hydroxide in water solution) was spread on the forearm skin of a human
subject using
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a thin wood stick. The thickness of the layer was about 0.2 mm (approximately
20 mg/cm2).
A piece of the sheet made in Step 4, about 2 cm X 3 cm, was placed on top of
the vehicle
liquid already on the skin area, with the gauze side in touch with the vehicle
liquid. A
Kleenex tissue was used to tap on the sheet and surrounding area to ensure
intimate contact
and remove excess vehicle liquid outside the sheet area. Forty-five minutes
after the
commencement of the application, the sheet was lifted and the skin under it
was scratched
with the end of a straightened paper clip. The skin was deeply numb. The sheet
had stronger
adhesion to skin during the test than that in Step 7, suggesting more adhesion
agent in the
vehicle solution, Carbopol 981, did contribute to stronger adhesion between
the sheet and the
skin.
[0094] In the above systems and experiments, PVA was both a fastening agent
and an
adhesion agent. Carbopol 981, neutralized with sodium hydroxide, was an
adhesion agent.
The 3M 9832 polyurethane tape was the MVTR control layer of the solid sheet,
and the
gauze layer was the later diffusion layer and the fluid retention layer.
Tetracaine was the
active drug, and the liquids in Step 7 and Step 8 were vehicle liquids.
Example 4
[0095] 3.04 grams of the 25% PVA solution made in Step 1 of Example 3, 4.55
grams
rubbing alcohol, and 0.51 grams tetracaine base were mixed to yield a clear
solution
containing 6.3% tetracaine and 9.4% PVA. Approximate 6.7 grams of the solution
(about 7
mL) was dispensed evenly on to a 190 cm2 gauze-3M 9832 laminate sheet (same as
the sheet
made in Step 3 of Example 3). The sheet was dried in the oven. The dried sheet
contained
about 2.2 mg tetracaine and 3.3 mg PVA per cm2.
[0096] The following experiment was conducted to test the wear property and
the anesthesia
effect of the system using distilled water as the vehicle liquid.
[0097] Distilled water was placed into a spray bottle and sprayed on a human
subject's left
forearm skin. The skin area was covered with densely populated beads of the
distilled water,
but the water did not quite form a continuous layer.
[0098] A piece of the laminated sheet (approximate 2 x 3 cm), which contained
2.2 mg
tetracaine and 3.3 mg PVA per cm2, was placed on top of the distilled water
already on the
skin area, with the gauze side in touch with the distilled water. A Kleenex
tissue was used to
tap on the sheet and surrounding area to ensure intimate contact and remove
excess vehicle
liquid outside the sheet area. Forty-five minutes after the commencement of
the application, a
corner of the sheet was lifted and the skin under it was scratched with the
end of a
straightened paper clip. The skin was deeply numb. The sheet was allowed to
stay on the skin
,1
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for a total of two hours before it was removed. At the end of the two hour
period, the sheet
still adhered to the skin very well, and it had to be peeled off the skin. The
peeling force
needed was slightly higher than that needed to lift a "post-it" stick note
from a skin surface.
The skin area was numb for at least four hours following the removal of the
sheet.
[0099] In the system of this Example, there was no adhesion agent in the
vehicle liquid. The
only adhesion agent in the system was the PVA impregnated in the sheet, which
dissolved
into the distilled water after the sheet and the distilled water were brought
into contact with
each other. The PVA also served as the fastening agent.
[0100] In this Example, although the distilled water sprayed on the skin only
covered the skin
area with water beads and did not quite form a continuous layer, the entire
skin area under the
sheet was completely numb after the test period, even at places not originally
covered by the
water beads. That was because the gauze layer (lateral diffusion layer) was
very absorbent to
the vehicle liquid. After the sheet was applied, the water beads absorbed into
the gauze layer
quickly spread within the gauze layer to make the entire gauze layer "wet".
The entire skin
area was thus covered by the vehicle liquid without any "dry" spots. As the
result, the entire
skin area covered by the sheet was in contact with tetracaine and water. The
skin area was
numb without a spot that was not numb.
[01011 Therefore, another important feature of the systems of the current
invention is that the
sheet comprises a layer that is absorbent to the vehicle liquid, or is capable
of help spread the
vehicle liquid after the sheet is applied over the vehicle liquid between the
sheet and the skin.
[0102] In the gauze-3M 9832 polyurethane tape laminate sheet of this Example,
the gauze
has practically no resistance to water vapor transmission (equivalent to
extremely high
MVTR) while the 3M 9832 poly urethane tape has an MVTR of 800 gram/m2/24hour
(according to 3M). The MVTR of the entire laminate sheet thus is very close to
800
gram/m2/24hour. In this case, the 3M 9832 polyurethane tape functioned as the
MVTR
control layer.
Example 5
[0103] The sheet in this Example was the same as that in Example 4.
[0104] The following experiment was conducted to test if the same sheet can be
used
multiple times.
[0105] Distilled water was placed into a spray bottle and sprayed on the
dorsal side of the left
hand of a human subject. The skin area was covered with densely populated
beads of the
distilled water, but the water did not quite form a continuous layer. A piece
of the laminated
sheet (approximate 2 x 3 cm), which contained 2.2 mg tetracaine and 3.3 mg PVA
per cm2,
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was placed on top of the distilled water already on the skin area, with the
gauze side in touch
with the distilled water. A Kleenex tissue was used to tap on the sheet and
surrounding area
to ensure intimate contact and remove excess vehicle liquid outside the sheet
area. Sixty
minutes after the commencement of the application, the sheet was removed from
the skin and
the skin under it was scratched with the end of a straightened paper clip. The
skin was deeply
numb. The sheet stayed on the skin for the entire 60 min test period. The
removed sheet was
placed on a piece of paper with the gauze side facing up, so that any residual
water in the
sheet was allowed to evaporate. After about 30 minutes, distilled water was
sprayed onto
another part of the dorsal side of the hand skin of the human subject. The
sheet used in the
first test was applied on the skin with the water beads in between the sheet
and the skin. After
60 minutes, the sheet was removed from the skin. The skin surface underneath
it was deeply
numb, and the sheet stayed adhered on the skin for the entire 60 minutes. The
same test was
repeated for the 3, 4th, and 5th time (the 5th time was on forearm skin of the
human subject).
In the 3rd and 4th tests, the skin under the sheet was deeply numb after the
60 minute
application, and the sheet stayed adhered to the skin well for the entire 60
minute test
durations. In the 5th test, the sheet stayed adhered well to the skin for the
entire 60 minute
test period, but the skin under the sheet was not completely numb after the 60
minute
application. However, the skin became completely numb about 30 minutes after
the sheet was
removed. Each of the 5 treated skin areas was numb for at least 5 hours.
[0106] The fact that the same sheet was able to produce deep skin anesthesia
at least 4 times
suggests that it is possible to manufacture a sheet that can be used by the
patient multiple
times. This would reduce the cost to the patients.
[0107] The gauze layer in the sheet was the lateral diffusion layer for
achieving even
distribution of the vehicle liquid on the skin. Therefore, although the
sprayed water beads did
not cover the target skin area continuously, water covers the entire target
skin area
continuously after the sheet was applied because water quickly spread
laterally within the
sheet so the entire gauze layer, and the skin area, was "wet" without a "dry"
spot. As the
result, the entire skin area covered by the sheet was in contact with
tetracaine and water. The
skin area was numb without a spot that was not numb.
Example 6
[0108] In a sheet liquid combination system of the current invention, the
sheet itself (without
the vehicle liquid) doesn't have to be adhesive to the skin because the
vehicle liquid itself or
the combination of sheet and liquid (as in Examples 4 and 5) can provide the
adhesiveness.
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However, it can be advantageous to have a sheet that is adhesive to the skin
even without the
vehicle liquid.
[0109] In a sheet liquid combination system in which the sheet is adhesive to
the skin without
the vehicle liquid, the vehicle liquid is still needed to deliver the drug at
the desired rates.
However, the sheet can be large enough so that its peripheral area can be used
to help adhere
the sheet to the skin while its central part can be used, in conjunction with
the vehicle liquid,
to deliver the drug. To use such a system, the patient or caregiver can
applied the vehicle
liquid over the target skin area, then apply a sheet that is large enough to
cover not only the
area covered by the vehicle liquid applied but also some surrounding skin area
not covered by
the vehicle liquid. Thus, the central area of the sheet is over the target
skin area covered with
the vehicle liquid, but the peripheral area of the sheet is in direct contact
with the skin area
not covered by the vehicle liquid. In the area where the sheet is over the
vehicle liquid, the
drug is delivered at the desired rate. However, in the area where the sheet is
in direct contact
with the skin without the vehicle liquid, the drug is delivered at much slower
rate or not
delivered at all for practical purposes, as the vehicle liquid is necessary
for the drug to be
delivered at the desired rate. Because the sheet is adhesive to the skin
without the vehicle
liquid, the peripheral area of the sheet can serve as a non-drug-delivery
adhesive area to help
keep the sheet on the skin.
[0110] There are several advantages of this system: (1) the adhesion of the
sheet on the skin
is not totally dependent on the vehicle liquid, so that the sheet can adhere
to the skin better
and/or for longer duration. (2) for a target skin area of any shape and size,
a piece of sheet
can be cut so it has such a shape and size that it can have an area for the
delivery of the drug
into the target skin area as well as an area for adhering the sheet on the
skin.
[0111] Some transdermal patches have distinct central areas for drug delivery
and peripheral
adhesive area to hold the patch on the skin. Those patches are not desirable
for target skin
areas with irregular shapes or sizes. For example, it is difficult to use a
drug delivery patch
with a 4" X 4" drug delivery area surrounded by peripheral adhesive area to
cover a target
skin area of 1" X 6". With the current system, the user can simply cut a 3" X
8" strip out of a
large sheet, apply the vehicle liquid over the 1" X 6" target skin area, and
apply the 3" X 8"
sheet over it. The 1" wide rectangular ring surrounding the 1" X 6" area can
serve as the
peripheral adhesive. This is an important versatility for target skin areas
with irregular sizes
and shapes. For example, the skin areas suffering from post herpetic neuralgia
for different
patients can have vastly different shapes and sizes.
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[0112] The following system was manufactured and tested on human skin as an
example and
one of the possible embodiments of this idea.
[0113] All percentages are in weight unless specified otherwise.
[0114] Step 1. A solution (Solution A) with the following composition was
made: 6.4%
polyvinylpyrrolidone, USP (PVP, molecular weight 40,000, Amresco), 3.6% poly
ethylene
glycol 400 (PEG 400, Spectrum Chemical), 90% rubbing alcohol.
[0115] Step 2. A second solution (Solution B) with the following composition
was made:
6.4% poly vinyl pyrrolidone, USP (PVP, molecular weight 40,000, Amresco), 3.6%
poly
ethylene glycol 400 (PEG 400, Spectrum Chemical), 6% tetracaine base, USP
(Spectrum
Chemical), 84% rubbing alcohol.
[0116] Step 3. An 6 cm X 10 cm gauze (Dusoft Non-woven Sponges, No. 84148,
single ply)
was placed on a sheet of release liner. Approximately 1.5 gram of the Solution
A made in
Step 1 was evenly dispensed onto the gauze. The solution-soaked gauze on the
release liner
was then placed into an oven to evaporate off the isopropyl alcohol and water.
[0117] Step 4. Approximately 1.5 gram of the Solution B made in Step 2 was
evenly
dispensed onto the dried gauze (still on the release liner) made from Step 3.
The gauze was
again placed into the oven to evaporate off the isopropyl alcohol and water.
The dried gauze
now had approximately 3.2 mg PVP, 1.8 mg PEG 400, and 1.5 mg tetracaine per
cm2.
[0118] Step 5. A sheet of the 3M 9832 polyurethane tape (with the non-adhesive
side on a
release liner) was laminated on top of the dried gauze (which was still on
another release
liner) made in Step 4, with the adhesive side of the 9832 tape adhering to the
dried gauze.
The dried gauze now was sandwiched between the release liner and the 9832
tape.
[0119] Step 6. Separately, a vehicle liquid with the following ingredients was
made: 4%
PEG 400, 6% PVP, 0.5% carbopol 981, NF, 0.23% sodium hydroxide, 89.27%
distilled
water.
[0120] The following experiment was performed to test the system made above.
[0121] Step 7. A layer of the vehicle liquid made in Step 6 was spread on a
human subject's
left forearm skin to cover a 2 X 2 cm area. The thickness of the layer was
such that the layer
was barely continuous (about 0.2 mm thick).
[0122] Step 8. A 4 cm x 5 cm piece was cut from the laminated sheet made in
Step 5, and the
release liners were removed. The sheet piece was then placed on top of the
vehicle liquid
layer already on the skin, with the gauze side in touch with the vehicle
liquid. The central
area of the sheet piece was over the vehicle liquid, but the peripheral area
was in contact with
dry skin area. The sheet piece, especially the peripheral area, was gently
massaged to ensure
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good contact. The sheet piece, including the peripheral area, stayed adhered
to skin for the
entire 45 minute test period.
[0123] Step 9. Forty-five minutes after the commencement of the application,
the sheet piece
was removed from the skin. The skin area that was covered by both the vehicle
liquid and the
sheet was deeply numb, but the skin area covered by the sheet only without the
vehicle liquid
was not numb at all.
[0124] Step 10. Separately, a 2 cm X 2 cm piece was cut from the laminated
sheet made in
Step 5, and the release liners were removed. The 2 cm X 2 cm sheet piece was
applied to a
human subject's left forearm skin directly without the vehicle liquid. After
90 minutes, the
sheet piece still adhered to the skin well. The sheet piece was then removed
from the skin.
The skin under the sheet piece was not numb at all. This result demonstrated
that the
presence of the vehicle liquid was necessary to deliver tetracaine at high
enough rates to
numb the skin.
Example 7
[0125] In this Example, the system for anesthetizing the skin is similar to
that in Example 1,
except that the sheet also comprises polyvinyl pyrrolidone (PVP) (e.g. PVP
with molecular
weight of 40,000, available from Amresco) at 2 mg/cm2 as both a fastening and
an adhesion
agent. Once the sheet is brought into contact with the vehicle liquid, PVP
would dissolve
into the vehicle liquid. The presence of PVP in the vehicle liquid would
increase the
adhesion between the skin and the sheet.
Example 8
[0126] The system for reducing the pain associated with post herpetic
neuralgia is similar to
that in Example 4 or 5. Because the target skin area is also suffering from
allodynia (hyper-
sensitive skin, where even a light touch can cause excruciating pain), the
application of the
vehicle liquid on the skin with a Q-tip or stick can cause severe pain to the
patient and thus is
not desirable. Therefore, an appropriate quantity of the vehicle liquid is
applied on the sheet
instead of skin. The sheet is then applied on the target skin area, with the
side with the
vehicle liquid in contact with the skin. More specifically, the vehicle liquid
is spread on the
sheet with a spatula in a quantity of approximately 20 mg/cm2. The sheet is
then applied onto
the skin area suffering from the pain associated with post herpetic neuralgia.
The sheet is
maintained on the skin area for 60-240 minutes before it is removed.
Significant pain
reduction would start within the 60 minute application time, and would last up
to 6-10 hours
(in non-facial skin) after the sheet is removed from the target skin area. The
skin area would
be dry when the sheet is removed, since water in the vehicle liquid under the
sheet would
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have evaporated through the sheet and the sheet would have the "dry-ending"
MVTR. To
obtain around-the-clock pain control (or close to it), the patient would use
the system every 8-
12 hours. If the application time is 60 minutes, the skin area is covered with
the sheet for
only two to three hours in a 24 hour period. Around-the-clock pain control
with only two to
three hours a day of skin occlusion is an important advantage, because it
means little, if any,
skin irritation, discomfort, or inconvenience would occur.
Example 9
[0127] In this Example, the patient uses the same system to treat post
herpetic neuralgia as
described in Example 8, except the patient re-uses the same sheet at least
twice, in a manner
similar to that described in Example 5.
Example 10
101281 This Example describes a three-component system for reducing
neuropathic pain with
capsaicin without the skin burning sensation.
[0129] Qutenza capsaicin patch is approved for treating pain associated with
post herpetic
neuralgia. It may also be effective in treating other neuropathic pain, such
as diabetes-
induced neuropathic pain, in the skin or tissues close to the skin surface.
However, the high
concentration of capsaicin in the patch itself can cause a severe burning
sensation and pain.
This is why the patient's skin has to be pre-treated with a local anesthetic
product, such as an
EMLA cream, before the Qutenza capsaicin patch is applied. The patient
typically has to
wait in the clinic for one hour or longer for the pre-treatment, which
typically needs to be
performed by clinic personnel, to produce the numbing effect. After the
treatment when the
capsaicin patch is removed, the pain control by the local anesthetics
(lidocaine and prilocaine
in the case of EMLA) often does not last long enough (typically no longer than
1-2 hours), so
that patients can suffer from post-treatment burning sensation.
[0130] To address this problem with an embodiment of the current invention, a
three
component system is made. The first component is an oil-in-water emulsion
cream
containing tetracaine hydrochloride (in the aqueous phase, with a typical
concentration of 3%
of the total formulation weight), soybean oil (the oil phase, with a typical
concentration of
30% of the total formulation weight) and polyvinyl alcohol (PVA) (in the
aqueous phase,
with a typical molecular weight 20,000-60,000, and a typical concentration of
10% of total
formulation weight). Soybean oil is a good solvent for capsaicin. "Good
solvent for
capsaicin" in this disclosure means a solvent with a capsaicin solubility of
at least 100
mg/Liter. Vegetable oils, such as soybean oil, are good solvents for
capsaicin. The pH of the
cream (the aqueous phase) would be 5 (to be achieved with an acid, such as
hydrochloric
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acid, if necessary, but is not pH buffered), so that the tetracaine in the
formulation is stable
enough to give the formulation a shelf life of at least 12 months at room
temperature. The oil
phase is emulsified in the aqueous phase with the help of an emulsifying
agent. The viscosity
of the cream would be such that a 1 mm thick layer of the cream can be easily
applied and
maintained on the target skin area. The second component is a fabric sheet
material
impregnated with sodium borate and a pH modifying agent (base). The fabric
sheet is
designed to have a pre-determined capsaicin permeability. The 3'd component is
a capsaicin
patch, similar to the Qutenza capsaicin patch. To use the system, a layer of
the cream is
applied on the target skin. The second component sheet is then applied on top
of the cream
layer. The 31d component capsaicin patch is then applied on top of the rd
component sheet.
Once this configuration is in place, the pH modifying agent in the sheet (the
rd component)
would dissolve into the cream layer and increase its pH to 7.5 or higher, thus
making the
tetracaine in the cream layer much more skin- permeable (compared to when the
pH is low).
Tetracaine would permeate into the skin and would numb it within 60 minutes.
Meanwhile,
the sodium borate in the 2nd component sheet would also dissolve into the
cream layer and
crosslink the PVA, so that the cream layer is converted into to soft solid
layer within 60 min.
The capsaicin in the patch would have to permeate through the 2nd component
fabric sheet
and across the thickness of the cream layer (mainly utilizing the soybean oil
phase in the
cream, because capsaicin is very soluble in soybean oil but poorly soluble in
water) before
reaching the skin surface, but it would eventually reach the skin surface. If
the components
are designed correctly (e.g. proper fabric sheet capsaicin permeability,
thickness of the cream
layer, and soybean oil content in the cream), the skin can be numbed by the
tetracaine before
the capsaicin can cause burning sensation. After the treatment time (e.g. 90-
120 minutes), all
three components would be removed from the skin. Because the cream layer would
already
be solidified and attached to the sheet, it is automatically removed when the
sheet (and the
capsaicin patch) is removed, leaving no messy residue on the skin surface.
Because
tetracaine can produce a much longer analgesic effect after the dermal
delivery is stopped
than lidocaine or prilocaine, the post-treatment numbing effect can last as
long as 6-12 hours
(in non-facial skin). The patient therefore has a much lower chance of
suffering from the
post-treatment burning sensation. This system would allow the patient to come
to the clinic,
let the physician or nurse to put the system on the target skin area as
described above, and go
home. The patient can remove the system himself/herself after a pre-determined
time. This
approach would avoid the wait in the clinic.
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Example 11
[0131] Topical NSAID products such as the ones containing about 1.6%
diclofenac as the
active ingredient are used to treat pain associated with osteoarthritis of the
knee (OA of the
knee) and soft tissue injuries such as sprained ankle. For example, Pennsaid
diclofenac
solution is used to treat pain associated with OA of the knee. However, the
patient has to
apply 40 droplets of the solution on the knee, 4 times a day. The applied
solution can be
easily wiped off by objects (e.g. pants) unintentionally. The 4-times-daily
application is
inconvenient. A system of the current invention designed to mitigate the
problem has two
components. The first component is a diclofenac solution, similar to or the
same as the
Pennsaid solution. The second component is a sheet impregnated with an
adhesion agent and
having a dry-ending MVTR for the diclofenac solution. The sheet is also
stretchable (elastic).
To use the system, the user applies about 2 mL of said diclofenac solution on
the target knee
skin area, and then covers the skin area with the sheet. The adhesion agent
(e.g. poly vinyl
pyrrolidone or PVA) would dissolve into the diclofenac solution and make it
act as an
adhesive to properly adhere the sheet onto the skin. To achieve the desired
effect, the sheet
should be kept adhered to the normal human skin surface under normal ambient
conditions
for at least 15 min, and preferably at least 60 min. Volatile solvents in the
diclofenac solution
would slowly evaporate through the sheet. After the desired application time,
the sheet
would be removed from the skin. In this approach, the diclofenac solution is
protected from
unintentional removal and premature evaporation of the solvent (which stops
the drug
delivery), so that more diclofenac is delivered in each treatment. The
frequency of treatment
in each day can thus be reduced, which is more convenient to the patient and
can improve
patient compliance.
[0132] In this Example, the reason to use the sheet and liquid combination
system of the
current invention is not to improve the drug's stability. The advantage of
using the sheet and
liquid combination system in this case is being able to conveniently keep the
drug solution on
the skin for longer time, so the user doesn't have to wait for the solution to
dry on the skin or
worry about the solution being removed by clothing.
Example 12
[0133] The system for preventing the pain associated with laser tattoo removal
is similar to
that in Example 4. To use the system, a vehicle liquid (such as distilled
water) is sprayed on
the target skin area in a manner similar to that described in Example 4. The
sheet is then
applied onto the vehicle liquid layer already on the target skin area. The
sheet is maintained
on the skin area for 90 minutes before it is removed. The skin area would be
anesthetized,
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and the laser tattoo removal procedure can be performed with minimal or no
pain to the
patient. The skin area would be dry or almost dry when the sheet is removed,
since water in
the vehicle liquid layer would have evaporated through the sheet and the sheet
has the "dry-
ending" MVTR
Example 13
[0134] The system for reducing the pain associated with herpes zoster in the
acute eruptive
phase is similar to that in Example 3. To use the system, the vehicle liquid
is spread on the
sheet at a quantity of approximately 20 mg/cm2. The sheet is then applied onto
the skin area
suffering from the pain associated with herpes zoster in its eruptive acute
phase (with blisters
and/or rash). The sheet is maintained on the skin area for 60 minutes before
it is removed.
Significant pain reduction would start within the 60 minute application time,
and would last
several more hours after the sheet is removed from the target skin area. The
skin area would
be dry or almost dry when the sheet is removed, since most or all of the water
in the vehicle
liquid layer would have evaporated through the sheet and the sheet has the
"dry-ending"
MVTR.
Example 14
[0135] The system is similar to that in Example 13, except in this case the
vehicle liquid is in
a fine mist spray bottle and is sprayed either on the target skin area or on
the sheet.
Example 15
[0136] The system for reducing the pain associated with carpal tunnel syndrome
is similar to
that in Example 5. To use the system, the vehicle liquid, which is contained
in a spray bottle,
is sprayed on the skin of the carpal tunnel area, at a quantity of
approximately 20 mg/cm2.
The sheet is then applied onto the skin area and maintained there for 60
minutes before it is
removed. For most patients in most situations, the skin area would be dry when
the sheet is
removed, since water in the vehicle liquid layer would have evaporated through
the sheet and
the sheet has the "dry-ending" MVTR. The application can be repeated at a
frequency and
for a number of times as adequate for significantly reducing the pain of the
individual patient.
The same sheet may be used multiple times in a manner similar to that
described in Example
5.
Example 16
[0137] The system for reducing the pain or headache associated with occipital
neuralgia is
similar to that in Examples 3-5. To use the system, the vehicle liquid is
spread on the target
skin area (typically the target skin area is the skin area over or adjacent to
the occipital
nerve), at a quantity of approximately 20 mg/cm2. The sheet is then applied
onto the skin
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area and maintained there for 90 minutes before it is removed. For most
patients in most
situations, the skin area would be dry when the sheet is removed, since water
in the vehicle
liquid layer would have evaporated through the sheet and the sheet has the
"dry-ending". The
application can be repeated at a frequency and for a number of times as
adequate for reducing
the pain or headache of the individual patient.
Example 17
[0138] The system for reducing back pain is similar to that in Examples 3-5,
except that the
vehicle liquid is soaked in a sheet of absorbent fabric, at a quantity of
approximately 20
mg/cm2, prior to the application. To use the system, the fabric sheet soaked
with the vehicle
liquid (wet sheet) is placed on the skin under which the back pain exists. The
tetracaine-
impregnated sheet is then applied over the wet sheet and maintained there for
90 minutes
before both sheets are removed from the skin. Tetracaine in the fabric sheet
would get
dissolved into the vehicle liquid and permeate into the skin. The application
can be repeated
at a frequency and for a number of times as adequate for reducing the back
pain of the
individual patient.
Example 18
[0139] The system for reducing pain associated with osteoarthritis of the knee
(OA of the
knee) is similar to that in Examples 3-5, except that four pieces of the sheet
(four sheets) are
used for each knee. To use the system, the vehicle liquid is applied on the
front, back, and
sides of the knee suffering from OA of the knee, at a quantity of
approximately 20 mg/cm2.
One sheet each is applied to each of the front, back, and two sides of the
knee, over the
applied vehicle liquid, so that four pieces of the sheet are used for each
knee. The sheets are
maintained there for 90 minutes before removal. The application can be
repeated at a
frequency and for a number of times as adequate for reducing the pain of the
individual
patient.
Example 19
[0140] The system and method in this Example are similar to that in Example
18, except in
this case the purpose is to treat pain associated with rheumatoid arthritis of
the knee.
Example 20
[0141] The system for reducing pain associated with sprained joints, including
sprained
ankle, knee, or shoulder, is similar to that in Examples 3-5, except the
number of pieces of
the sheet used for the joint can be varied depending on the size and the
curvature of the joint.
To use the system, the vehicle liquid is applied on the skin area over the
injured joint, at a
quantity of approximately 20 mg/cm2. One or more sheets are applied to the
skin area. The
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size and number of the pieces of the skeet used are determined by factors such
as the size of
the joint and the curvature of the skin area, to maximize comfort and minimize
the
interference with joint movement and potential of separation of the sheet(s)
from the skin.
The sheet(s) is maintained there for 90 minutes before removal. The
application can be
repeated at a frequency and for a number of times as adequate for reducing the
pain of the
individual patient.
Example 21
[0142] In this Example, the systems and methods for reducing back pain, pain
associated
with OA of the knee, rheumatoid arthritis of the knee, and sprained joints,
including sprained
ankle, knee, or shoulder are the same as that in Examples 17-20. In addition,
a ThermaCare
brand air-activated heat wrap is applied over the sheet which is already
applied on the skin.
The local heating can increase the permeability of the skin to tetracaine and
help dirve the
tetracaine into deeper tissues, which may mean better clinical results.
Example 22
[0143] The systems and medical conditions to be treated with the systems are
similar to those
in Examples 12-20, except that the drug is lidocaine and the application time
can be 2-12
hours, and also can be 5-12 hours.
Example 23
[0144] The system for reducing pain associated with scalded skin is similar to
that in
Example 4 or 5. To use the system, the vehicle liquid is sprayed on the skin
area over the
scalded skin area or on the sheet. The sheet(s) is applied on the scalded skin
with the vehicle
liquid between the sheet and the skin, and maintained there for 60 minutes
before removal.
The application can be repeated when or if the pain comes back.
Example 24
[0145] The system for reducing pain associated with scalded or burned skin is
similar to that
in Example 4 or 5 (where the adhesion agent is impregnated in the sheet),
except that the
local anesthetic agent is lidocaine. In this case, the scalded or burned skin
area is so damaged
that the stratum corneum layer (the main barrier layer of the skin) is all or
mostly damaged,
and there is visible bodily fluid oozing out of the area. To use the system,
the sheet is directly
applied to the skin area without the vehicle liquid, and maintained there for
a period of time
that offers a good balance between the need of pain control and wound care
(i.e. between the
need of treating the wound with anti-infection and/or wound healing medication
and the need
of the wound to be exposed to air). The bodily fluid oozing out of the wound
skin would
serve as the vehicle solution here to dissolve the tetracaine in the sheet and
deliver it into the
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wounded skin. The adhesive agent impregnated in the sheet would dissolve into
the bodily
fluid and provide the adhesion for keeping the sheet on the skin.
Example 25
101461 The system for reducing pain associated with scalded or burned skin is
similar to that
in Example 24, except that the sheet comprises a lidocaine-ion exchange resin
complex
instead of un-complexed lidocaine. The scalded or burned skin area is so
damaged that there
is visible bodily fluid oozing out of the area. To use the system, the sheet
is directly applied
to the skin area without the vehicle liquid, and maintained there for a period
of time that
offers good balance between the need of pain control and wound care (i.e.
between the need
of treating the wound with anti-infection and/or wound healing medication and
the need of
the wound to be exposed to air). The ions in the bodily fluid exchange out the
lidocaine
molecules in the lidocaine-ion exchange resin complex impregnated in the
sheet, so the
lidocaine release is controlled and extended. The patient thus enjoys a longer
pain relief
effect ad lower risk of lidocaine exposure than he/she would if a lidocaine
hydrochloride
solution is directly applied to the scalded or burned skin. Optionally, an
adhesive agent can
be impregnated in the sheet, and can dissolve into the bodily fluid and
provide the adhesion
for keeping the sheet on the skin.
Example 26
[01471 In this Example, a roll of absorbent paper (or other fabric) is soaked
in the vehicle
liquid which comprises an adhesion agent and is contained in a container. The
roll of
absorbent paper is made of many pre-cut pieces that are rolled in a way that
when one piece
is pulled out from the container, it brings up the next piece. This
arrangement is similar to
some baby wipe products or Kleenex tissues in a box. Alternatively, the roll
of the absorbent
paper is a continuous roll with periodical perforation or partial cuts for
easy tearing of the
pieces along the perforation lines. The container may have an attached sharp
edge to
facilitating the tearing. To use the system, the user pulls a piece of the
vehicle liquid-soaked
absorbent paper out of the box and lays it on the target skin area. The user
would then apply
the drug-impregnated sheet (similar to that in previous Examples) on top of
the vehicle
liquid-soaked absorbent paper and maintain it there for the desired duration
of dermal drug
delivery. Once the sheet is on top of the vehicle liquid-soaked absorbent
paper which is on
the target skin area, the drug impregnated in the sheet would dissolve into
the vehicle liquid
which helps deliver the drug into the skin. The sheet can have the "dry-
ending" MVTR so
that at the end of the application period, there is little or no liquid under
the sheet.
Al
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Example 27
[0148] Production and Testing of a Laminated Sheet Impregnated with Tetracaine
base (TC)
and Polyvinyl Alcohol (PVA)
[0149] Step 1. 176.2 gram rubbing alcohol was mixed with 22.4 gram of a 25%
PVA
solution (25% PVA, 75% water by weight) to form a "blank loading solution".
The blank
loading solution contained about 2.82% PVA and had a density of about 0.91.
[0150] Step 2. 0.35 g tetracaine base (TC) was added into 49.72 gram of above
blank
loading solution, and completely dissolved, to form TC Loading Solution One
which
contained 0.7% TC, 2.8% PVA, and had a density of about 0.91.
[0151] Step 3. 15 mL (about 13.65 g) TC Loading Solution One was dispensed
onto 190 cm2
fabric gauze (single ply, Dusoft 84148 from Derma Sciences) placed on a
plastic release liner
(3M9956). The solution soaked fabric was allowed to dry overnight at room
temperature.
This "loaded" fabric had 0.5 mg TC and 2 mg PVA/cm2.
[0152] Step 4. 22.49 g TC Loading Solution One was mixed with 15.02 g blank
loading
solution to form TC Loading Solution Two which contained 0.42% TC and 2.8%
PVA. Its
density was about 0.91.
[0153] Step 5. 15 mL (about 13.65 g) TC Loading Solution Two was dispensed
onto 190
cm2 fabric gauze (single ply, Dusoft 84148 from Derma Sciences) placed on a
plastic release
liner (3M9956). The solution soaked fabric was allowed to dry overnight at
room
temperature. This "loaded" fabric had 0.3 mg TC and 2 mg PVA/cm2.
[0154] Step 6. The air-dried fabric sheets from Steps 3 and 5 were placed into
an oven with
temperatures cycling between approximately 50 and approximately 60 C and
removed from
the oven after about 30 min. to evaporate any remaining solvent not evaporated
during the
room temperature drying process.
[0155] Step 7. The heat dried fabric sheets from Step 6 were laminated to a
polyurethane
tape (3M9834) using the tape's adhesive. The laminated sheets had 0.5 mg TC+2
mg
PVA/cm2 and 0.3 mg TC+2 mg PVA/ cm2, respectively. The sheets made in Step 7
can be
used as the sheet in the "Sheet Liquid Combination" of the current invention.
The TC was the
active drug, PVA was the fastening agent as well as the adhesion agent. The
fabric layer had
the lateral diffusion function and can serve as the "lateral diffusion layer".
The fabric layer
was also the "liquid retention layer. The poly urethane tape was the MVTR
control layer.
[0156] Step 8. On the day after Step 7, the following skin test was conducted:
Distilled water
droplets were sprayed onto the dorsal side of a human subject's hand. A piece
(1 cm x 2 cm)
of the laminated sheet made in Step 7 containing 0.3 mg TC+2 mg PVA per square
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centimeter was placed on the wet skin with the fabric side of the sheet in
contact with the
skin. In this and other Examples, when a fabric-film laminated sheet is said
to be placed on
the skin, it always means the fabric side is placed in contact with the skin.
A paper tissue was
used to tap on the outer face of the sheet and surrounding area of skin to
ensure good contact
and remove excess water. At 45 min from the start of the application, the
sheet was lifted and
the skin under it was poked with the end of a straightened paper clip. In this
and other
Examples, skin anesthesia, or numbness, was tested by the poking or scratching
with an end
of a straightened paper clip, unless specified otherwise. Similar testing
methods are known to
those of skill in the art. The skin area was almost completely numb. At 60
min, the sheet was
removed from the skin. The skin area treated by the sheet was completely numb.
The sheet
adhered to the skin very well for the entire 60 min test period.
[01571 Step 9. One week after Step 7, the sheets made in Step 7 were each cut
into halves
and the resulting four pieces of sheets were individually wrapped in aluminum
foil. One of
the 0.3 mg TC+2 mg PVA/ cm2 pieces and one of the 0.5 mg TC+2 mg PVA/cm2
pieces were
placed into a Styrofoam box, which was placed into an oven with temperatures
cycling
between about 63 and about 68 C (referred to as 65 C hereafter for
simplicity). The
remaining pieces were stored at room temperature. After 11 days, the pieces in
the oven were
removed from the oven and stored at room temperature. Two days later, all four
pieces were
tested for their skin anesthetizing ability using a method similar to that in
Step 8. The results
were as follows:
Sheet Storage condition Skin numbness after
60 min treatment
0.5 mg TC+2 mg PVAJ 11 days at 65 C, 9 days Not numb
cm2
at room temperatures
0.5 mg TC+2 mg PVA/ 20 days at room Numb*
cm2
temperatures
0.3 mg TC+2 mg PVA/ 11 days at 65 C, 9 days Not numb
cm2
at room temperatures
0.3 mg TC+2 mg PVA/ 20 days at room Numb*
cm2
temperatures
*The skin area treated by the unheated sheet containing 0.5 mg+2 mg PVA/cm2
felt more
profound numbness than that by the unheated sheet containing 0.3 mg+2 mg PVA/
cm2,
suggesting that the former sheet delivered more TC into the skin.
[01581 These results suggest that the lamination adhesive of the 3M9834 tape
can interact
with the TC formulation after long term storage. By a rule of thumb that drug
degradation
rate increases by a factor of 3 for every 10 C storage temperature increase,
storage at 65 C
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for 11 days is approximately equivalent to storage at room temperature for
about 2.5 years.
Therefore, the above results suggest that if 3M9834 tape is used in the sheet,
the sheet's
anesthetizing ability can be compromised after long term storage at room
temperature.
Example 28
[0159] As suggested by the results of the previous Example, it is possible
that certain
adhesives used to laminate the fabric layer to the polyurethane film
(lamination adhesives)
may interact with tetracaine chemically or physically such that the tetracaine
impregnated
sheets' ability to produce skin anesthesia is compromised after long-term
storage. The
following experiments were conducted to select a tape and its adhesive that do
not
compromise the anaesthetic effect of the tetracaine.
[0160] A blank loading solution with the following components was made:
70% isopropyl alcohol solution 176.2 gram
(70% isopropyl, 30% water, by volume)
25% PVA solution 22.4 gram
(25% PVA, 75% water)
The density of this loading solution was about 0.91 and it contained about
2.82% PVA.
Three tetracaine loading solutions with the following compositions were made:
Tetracaine Loading Solution A: 1.4% tetracaine base, 98.6% blank loading
solution.
Tetracaine Loading Solution B: 0.7% tetracaine base, 99.3% blank loading
solution.
Tetracaine Loading Solution C: 0.42% tetracaine base, 99.58% blank loading
solution.
[0161] Fifteen mL Tetracaine Loading Solution A was dispensed evenly onto 190
cm2 of an
absorbent fabric (Derma Sciences Dusoft 84148, single ply) resting on a
release liner. The
solution soaked fabric was placed on a flat surface in an oven with
temperatures cycling
approximately between 62 and 68 C for 45 min to evaporate off the solvents.
The dried
fabric contained 1 mg tetracaine and 2 mg PVA per square centimeter.
[0162] The same procedure was repeated with Tetracaine Loading Solutions B
and C,
respectively, to produce fabric sheets impregnated with 0.5 mg tetracaine and
2 mg PVA per
square centimeter, and 0.3 mg tetracaine and 2 mg PVA per square centimeter,
respectively.
[0163] Each of the dried fabrics above was cut into three equal parts which
were laminated to
three polyurethane tapes: 3M9832, 3M9834, 3M9948, respectively, with the dried
fabric
adhered to the adhesive side of the tape. Nine different laminated sheets were
thus produced.
[0164] Each of the nine laminated sheets was cut into half. One of the halves
was wrapped in
aluminum foil and stored at room temperature. The other halves were wrapped in
aluminum
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foil and placed into an oven at a temperature cycling between approximately 62
and
approximately 68 C (for simplicity, the 62-68 C cycling temperatures will be
referred to
hereafter as 65 C).
[0165] After 11 days, all the samples were removed from the oven and some of
the 18
samples (9 stored at room temperature and 9 stored at 65 C) were tested on a
human
subject's skin for skin anesthesia with the following method: A 1 cm x 2 cm
piece of each of
the test sheets was applied onto the skin surface of the subject which was
covered with fine
distilled water droplets sprayed from a spray bottle. A paper tissue was used
to gently tap the
sheet and surrounding area to ensure good sheet-skin contact and remove water
from outside
the sheet area. After 60 minutes, the sheet was removed and skin anesthesia
was tested by
poking with the end of a straightened paper clip. The samples tested, the skin
sites, and
anesthesia results are summarized in the following table.
Tetracaine/cm2 PVA/cm2 Type of Storage Skin site Skin
(mg/cm2) (mg/cm2) tape in temperature
numbness
laminate after 60 min
application
0.3 2 3M9832 11 days at Dorsal Numb
65 C hand
0.3 2 3M9834 11 days at Dorsal Not numb
65 C hand
0.3 2 3M9832 Room Dorsal Numb
hand
0.5 2 3M9832 11 days at forearm Numb
65 C
0.5 2 3M9834 11 days at forearm Not numb
65 C
0.3 2 3M9948 11 days at Dorsal Not numb
65 C hand
1 2 3M9834 11 days at Dorsal Not numb*
65 C hand
0.3 2 3M9948 Room Dorsal Not
hand numb**
0.3 2 3M9832 Room Dorsal numb
hand
*This skin site was numb when tested at 120 minutes (60 minutes after the
sheet was removed from
the skin site), suggesting that the anesthetizing ability had not been totally
destroyed by the storage at
65 C for 11 days. **The skin site was numb when tested at 180 mm.
[0166] One can see from the above results that: (1) sheets with the 3M9832
tape, regardless
of the storage temperature or tetracaine quantity, maintained anesthetizing
ability; (2) sheets
with 3M9834 tape, after 11 days at 65 C, regardless of tetracaine quantity,
lost anesthetizing
ability; (3) sheets with 3M9948 tape lost the anesthetizing ability after 11
days storage at 65
AS
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C, and similar sheets lost much anesthetizing ability after about 20 days of
room temperature
storage.
[0167] The purpose of storing the samples at 65 C was to estimate their long
term (years)
stability using a much shorter time period. As a rule of thumb in drug
stability tests, the rate
of drug loss increases by a factor of three for every 10 C that the storage
temperature is
increased. Therefore, the rate of drug loss at 65 C is approximately 80 times
higher than that
at 25 C, and storage at 65 C for 11 days is equivalent to approximately 2.4
years of storage
at 25 C. Although this is an estimation, it was effective to demonstrate that
different
lamination adhesives can have different impacts on the laminated sheets' long
term stability.
These results suggest that the sheets with 3M9834 or 3M9948 tapes will likely
lose
anesthetizing ability after 2.4 years of storage at room temperature, while
sheets with
3M9832 tape will not.
[0168] According to 3M, the 3M9832 and 3M9834 tapes use the same polyurethane
film, but
different adhesives. It follows that the loss of anesthetizing ability in
sheets with 3M9834
must be caused by 3M9834's adhesive. It is likely that the loss of
anesthetizing ability in
sheets with 3M9948 was also caused by its adhesive. Since all three tapes are
medical grade
tapes and have otherwise similar properties, it is surprising that only
3M9832's adhesive does
not cause the loss of anesthetizing ability.
Example 29
[0169] Heat Lamination of Rayon- Polyester Blend Fabric to Polyurethane Film
[0170] Example 28 demonstrated that the lamination adhesive can potentially
interact with
the tetracaine formulation to compromise anesthetizing ability. While
selecting a lamination
adhesive that does not compromise the anesthetizing ability is one approach to
dealing with
this potential problem, another is to laminate the fabric layer and the
barrier film together by
heat, avoiding the use of lamination adhesive completely. The following
Example
demonstrates such a heat lamination process.
[0171] Heat press used: Seiki Technology, Type SK-HP3
[0172] Materials to be heat laminated: a rayon polyester blend fabric (Derma
Sciences Dusoft
84122, same material as Dusoft 84148, single ply) and a polyurethane film (3M
9832F).
[0173] For each of the tests (with different heat press heating temperature
settings) the fabric
and film were assembled as described in Example 33 and heat pressed. The
heating
temperature and duration setting, along with the observed results, are
summarized in Table 1.
Table 1
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Heating temp. setting Heating Duration setting Observation
260 F 2 seconds Fabric and film had a weak bond,
but were still separable
270 F 2 seconds Fabric and film had a weak bond,
but were still separable
280 F 2 seconds Fabric and film had a weak bond,
but were still separable
290 F 2 seconds Fabric and film bonded, but still
separable
300 F 2 seconds Fabric and film bonded, barely
separable
310 F 2 seconds Fabric and film bonded, difficult to
separate, but still separable
320 F 2 seconds Fabric and film bonded, very
difficult to separate
330 F 2 seconds Fabric and film bonded, not
separable
No film damage was observed in any of the above tests.
[0174] Separately, tests were conducted for heat laminating the same rayon
polyester blend
fabric (Derma Sciences Dusoft 84148) with a different polyurethane film
(America Polyfilm,
Inc. MT1001-AM). The method was similar to the previous tests. The results are
summarized in Table 2.
Table 2
Heating temp. setting Heating Duration setting Observation
330 F 2 seconds Bonded, but slight damage
to the film occurred
300 F 2 seconds Bonded, almost no damage
to the film observed
[0175] These results suggest that the rayon polyester blend fabric can be
laminated to a
polyurethane film with heat, but proper heating temperature and duration must
be used. The
lamination of the fabric and the film with heat eliminates the need to use
adhesive for
lamination, which could mean the avoidance of potential adverse interactions
between the
drug formulation and the lamination adhesive, as well as lower material costs
since a film
coated with adhesive is typically significantly more expensive than the film
purchased alone.
Example 30
[0176] Heat Lamination of Polyurethane Film to a Fabric Already Loaded with
Tetracaine
and PVA
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[0177] A piece of a rayon polyester blend fabric (Derma Sciences Dusoft 84148)
was loaded
with 0.3 mg TC and 2 mg PVA per square centimeter. The method of loading the
TC and
PVA was similar to that described previously.
[0178] The loaded fabric piece was laminated to a polyurethane film (3M 9832F)
with the
heat press (Seiki Technologies, Type SK-HP3) with heating temperature setting
of 330 F
and heating duration of 30 seconds. The heat lamination process was similar to
that described
previously.
[0179] The following skin test was conducted to determine if the 330 F
heating for 30
seconds destroyed the anesthetizing ability of the sheet: fine water droplets
were sprayed onto
the forearm skin of a human subject. A 1 cm x 2 cm piece of the above-
described heat-
laminated sheet was applied on the wet skin. After 60 min, the sheet was
removed from the
skin. The skin area was dry and deeply numb (as determined by poking with an
end of a
straightened paper clip).
[0180] The above experiment was repeated with the same fabric loaded with 0.5
mg and 2
mg PVA per square centimeter. After 60 min treatment with the laminated sheet,
the skin
area was also dry and deeply numb.
[0181] These results suggest that heating the TC+PVA formulation already
coated on the
fabric at 330 F for 30 seconds does not destroy the anesthetizing ability. It
should be noted
that this does not necessarily mean that no TC was degraded during the heating
process. It is
possible that some TC was destroyed in the heating process. Despite this,
however, enough
TC survived to maintain the desired anesthetic effect.
Example 31
[0182] Effect of Different Degrees of Occlusion on Skin Anesthesia Duration
[0183] A previously made fabric (Derma Sciences Dosoft 84148 rayon polyester
blend)
loaded with 1.98 mg TC and 4.74 mg PVA per square centimeter was laminated to
a
polyurethane tape (3M 9832) using the tape's adhesive. Fine water droplets
were sprayed
onto the forearm skin of a human subject. Two 1 cm x 2 cm pieces of the
laminated sheet
were applied on the wet skin. One of the two pieces was then covered with a
piece of
Scotch tape (3M) to produce better occlusion (lower MVTR). After 60 min, both
sheets
were removed from the skin. The skin area under the sheet that was covered by
the Scotch
tape was more moist than the other skin area, likely as a result of better
occlusion. Both skin
areas were deeply numb (as tested by poking with a straightened paper clip).
The numbness
of the skin areas was tested at the following time points:
6 hours (5 hours after sheet removal): both areas deeply numb.
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7 hours (6 hours after sheet removal): both areas deeply numb.
8 hours (7 hours after sheet removal): both areas lost most of the numbness.
There is
no difference in numbness between the two areas.
[0184] These results suggest that the occlusion produced by the 3M 9832 tape
is good
enough in terms of producing the anesthesia effect for an extended period of
time, and better
occlusion (lower MVTR) does not produce longer lasting anesthesia.
Example 32
[0185] Effect of High Temperature Storage on Anesthetizing Ability of the
Sheet
[0186] The following sheets were made before the skin test:
[0187] Sheet 1: A Dusoft 84148 fabric was loaded with 0.3 mg tetracaine base
(TC) and 2
mg PVA/cm2. The process of loading the TC and PVA was the same as that
described
previously. The dried loaded fabric was laminated to the 3M9832 tape using the
tape's
adhesive. The laminated sheet was stored in an oven with temperatures about
155 F for at
least 30 days.
[0188] Sheet 2: Same as Sheet 1, except that the fabric with loaded with 0.5
mg TC and 2 mg
PVA per cm2. The sheet was also stored in the oven with temperatures about 155
F for at
least 30 days.
[0189] Sheet 3: A Dusoft 84148 fabric loaded was with 0.5 mg tetracaine base
(TC) and 2
mg PVA/cm2. The dried loaded fabric was not laminated to any film and was
stored in the
oven with temperatures about 155 F for at least 30 days. The loaded fabric
was then
laminated to the 3M9832 tape using the tape's adhesive just before the skin
test below.
[0190] The following skin test was conducted:
[0191] Water was sprayed on the skin of the back of a human subject's hand.
Each of the
three sheets above, about 1 cm x 2 cm, was placed on the wet skin, with the
fabric side in
contact with the skin. After 60 min (t = 60 min), the sheets were removed from
the skin. Skin
anesthesia was measured by poking the skin area with the end of a straightened
paper clip at
each test time point, with the following results:
Time (from start of the Sheet 1 Sheet 2 Sheet 3
sheet application)
60 min Not numb Numb Numb
150 min* Numb Numb Numb
210 min Not numb Numb Numb
240 min Not numb Numb Numb
270 min Not numb Not numb Not numb
An
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*The human subject was involved in physical activities that caused significant
sweating
between t= 150 min and 210 min, which could have had the effect of reducing
the duration of
the anesthesia effect because increased blood circulation may increase the
speed of clearance
of TC from the skin areas.
[0192] These results suggest that (1) storing the fabric loaded with 0.5 mg TC
and 2 mg PVA
per cm2 at about 155 F for 30 days does not destroy the anesthetizing
ability, regardless of
whether the loaded fabric was laminated to the 3M9832 tape before or after the
high
temperature storage. (2). The same high temperature storage seemed to
significantly weaken
the anesthetizing ability of the laminated sheet containing 0.3 mg TC and 2 mg
PVA/cm2, so
the sheet (Sheet 1) only produced skin anesthesia that was delayed and of
shorter duration.
However, Sheet 1, with only 0.3 mg TC per cm2, may have had weaker
anesthetizing ability
than the other sheets to start with.
Example 33
101931 Separation of Heat Laminated Fabric-Polyurethane Film Laminate Caused
by the
Soaking of the Loading Solution
[0194] A fabric (Derma Sciences Dusoft 84148) was heat laminated to a
polyurethane film
(MedCo RTS 1716-11) with a heat press (Seiki Technologies, Type SK-HP3) with a
heating
temperature of 330 F and a heating duration of 2 seconds. The heat lamination
was done
after placing the polyurethane film RTS 1716-11 and the Dusoft 84148 together
between
sheets of a plastic release liner (in this Example, 3M9956), with the plastic
carrier layer of the
polyurethane film facing toward the heating plate of the heat press. The bond
was good and
the two materials were not separable. However, after the fabric layer of the
laminated sheet
was dispensed with a blank loading solution (18.6% of a 25% PVA solution,
81.4% rubbing
alcohol, 12 mL on 190 cm2) and the soaked laminate was allowed to dry at room
temperature
overnight, the fabric and the film became separable.
[0195] The heat lamination of the same fabric and film was repeated with the
same 330 F
heating temperature but several different heating durations: 2 seconds, 3
seconds, 4 seconds,
seconds, and 6 seconds. After dispensing the same blank loading solution onto
the fabric of
each of the sheets (1.5 mL for each 28 cm2 sheet) and drying the sheets in the
155 F oven for
one hour, all laminated sheets' film and fabric became separable.
[0196] These results suggest that the solvents in the loading solution can
cause the separation
of the film and fabric laminated together with 330 F heating temperature and
a heating
duration as long as 6 seconds.
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[0197] To explore whether higher heating temperature can produce a film-fabric
laminate
that can withstand the soaking of the loading solution without film damage,
the following
experiments were conducted: using the same method as described above, the RTS
1716-11
polyurethane film and the 3M9832F polyurethane film, respectively, were
laminated to the
Dusoft 84148 fabric using various heating temperatures and durations. The 3M
9832F film
had no carrier. A loading solution of 1.3% tetracaine base (TC), 98.7% of the
above blank
loading solution, was made. The loading solution contained about 1.3% TC and
4.6% PVA.
One and half mL of the loading solution was dispensed onto the fabric side of
each of the
laminated sheets (25 cm2 each sheet). The solution soaked sheets were placed
in a 155 F
oven for 60 min to evaporate off the solvents. The dried sheets were removed
from the oven
and allowed to cool to room temperature. Attempts were made to separate the
film and the
fabric of the dried sheets. The sheets were also examined for possible film
damage. The
heating temperature, heating duration, and test results are summarized in
Table 2 below.
Table 2
Film Heating Heating Film separable Film
temp duration from fabric? damage?
MedCo 330 F 3 sec Yes No
RTS1716-11
MedCo 340 F 3 sec Yes No
RTS1716-11
MedCo 350 F 3 sec Yes No
RTS1716-11
MedCo 360 F 3 sec Yes No
RTS1716-11
McdCo 370 F 3 sec Barely No
RTS1716-11
MedCo 380 F 3 sec No No
RTS1716-11
3M9832F 380 F 3 sec Yes Yes
101981 There results suggest that: (1) the Dusoft 84148 fabric and the MedCo
RTS1716-11
film heat laminated together with a 380 F heating temperature and a 3 second
heating
duration can withstand the soaking of the loading solution without separation.
The film can
withstand the heating temperature and duration without being damaged. (2) The
380 F
heating temperature and 3 second heating duration caused some film damage to
the
3M9832F. The 3M9832F film did not have a carrier layer while the RTS 1716 film
did have
a thick plastic carrier layer that was in the path of heat transfer from the
heating plate to the
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film. As a result, the 3M 9832F film might be exposed to higher temperature
during the heat
lamination process. It is possible that the damage to the 3M9832F film was
caused by that
higher temperature.
Example 34
[0199] Heat Laminating a Fabric and a Polyurethane Film with a 380 F Heating
Temperature and 3 Second Heating Duration and Effects of High Temperature
Storage
[0200] In this Example, a fabric was heat laminated to a polyurethane film to
form a
laminate, and TC and PVA were impregnated into the fabric side of the
laminate. The
anesthetizing ability of the TC and PVA impregnated sheet was tested. The
experimental
procedures are as follows:
[0201] Step 1. A fabric (Derma Sciences Dusoft 84148) was heat laminated to a
polyurethane film (MedCo RTS 1716-11) with a heat press (Seiki Technologies,
Type SK-
HP3) with heating temperature of 380 F and heating duration of 3 seconds. The
heat
lamination method used was similar to that described previously.
[0202] Step 2. A TC loading solution with the following composition was made:
0.86%
tetracaine base (TC), 99.14% of a blank solution (same as the blank loading
solution in
Example 33). This TC loading solution contained 0.86% TC and about 4.6% PVA,
and had a
density of about 0.91.
102031 Step 3. Twelve mL of the TC loading solution made in Step 2 was evenly
dispensed
onto the fabric side of the laminated sheet (190 cm2) made in Step 1. The
laminated sheet
with the solution was placed into an oven with a temperature of about 155 F
for 60 min to
evaporate off the solvents. The dried sheet was removed from oven and allowed
to cool to
room temperature. There was no damage to the film part of the laminated sheet,
and the
fabric and film were not separable. This dried sheet contained about 0.5 mg TC
and 2.7 mg
PVA per cm2.
[0204] Step 4. The sheet made in Step 4 was cut in half. One of the halves was
stored at
room temperature and the other half was placed into an oven at a temperature
of about 155 F
for the next 12 days.
[0205] Step 5. A 1 cm x 2 cm piece of the room temperature half sheet made in
Step 4 was
cut out from the larger sheet and placed onto the forearm skin area of a human
subject which
had already been covered with fine water droplets sprayed on with a spray
bottle. The fabric
side of the sheet was in contact with the skin. After 60 min, the sheet piece
was removed
from the skin. The skin area under the sheet was deeply numb as determined by
poking with
an end of a straightened paper clip.
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[0206] Step 6. After 12 days of storage in the 155 F oven, the half sheet
made and placed in
the oven in Step 4 was removed from the oven and allowed to cool to room
temperature. Four
days later, the anesthetizing ability of the sheet was tested with a method
similar to that used
in Step 5. The treated skin area was numb when tested at t= 60 min (60 min
from the
beginning of the sheet application) and t = 240 min.
[0207] These results show that after 12 days of storage at about 155 F, the
laminated sheet
does not lose its anesthetizing ability. There was no lamination adhesive in
the sheet in this
Example, so that potential interaction between the drug and the lamination
adhesive was
avoided.
Example 35
[0208] Sheets with Ahlstrom Fabric, With no Fabric, and With Add-On Barrier
Film
[0209] Step 1. A tetracaine (TC) loading solution with the following
composition was made:
2% TC, 32.7% of a 25% PVA:75% water solution, and 65.3% rubbing alcohol.
[0210] Step 2. 2.6 mL of the TC loading solution in Step 1 was evenly
dispensed onto a
polyurethane film with paper carrier (80 cm2, 3M9832F). The film covered with
the solution
was placed into an oven with a temperature of about 155 F for 30 min to
evaporate off the
solvents. This process coated the 3M9832F film with about 0.6 mg TC and 2.5 mg
PVA per
cm2, and caused the film to wrinkle a little on the paper carrier.
[0211] Step 3. 3 mL of the TC loading solution in Step 1 was dispensed evenly
onto the
fabric side of a 55 cm2 pre-heat laminated sheet [Ahlstrom SX567 polyester
fabric heat
laminated to McdCo RTS1716-11 polyurethane film (with plastic carrier).
Heating
temperature was 380 F, heating duration was 3 seconds, and the lamination
method was
similar to that described previously]. The solution loaded sheet was dried in
the same oven as
in Step 2 for 60 min to evaporate off the solvents. The resulting dried
laminated sheet had
about 1 mg TC and 4.1 mg PVA per cm2.
[0212] Step 4. The Ahlstrom SX567 polyester fabric was loaded with 3 mg TC and
3 mg
PVA per cm2. The loading method used was similar to that described previously.
[0213] The following skin tests were conducted:
Test 1
[0214] Fine water droplets were sprayed onto the skin of the back side of a
human subject's
hand. A piece of the polyester fabric loaded with 3 mg TC and 3 mg PVA per cm2
made in
Step 4 (1 cm x 2 cm, no barrier film) was placed on the wet skin. The fabric
was then covered
with a piece of a plastic film (about 3 cm x 4 cm, "Glad" brand Cling Wrap, a
common
kitchen item).
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Test 2
Fine water droplets were sprayed onto the forearm skin of a human subject. A
piece, 1 cm x 2
cm, of the 3M9832F film coated with 0.6 mg TC and 2.5 mg PVA per cm2, made in
Step 2,
was placed on the wet skin, with the side with TC and PVA coating in contact
with the skin.
Test 3
Fine water droplets were sprayed onto the forearm skin of a human subject. A
piece, 1 cm x 2
cm, of the laminated sheet made in Step 3, containing about 1 mg TC and 4.1 mg
PVA per
cm2, was placed on the wet skin.
[0215] After 60 min (t = 60 min), all three sheets were removed from the skin
areas. It was
observed that the skin area in Test 1 was still wet, but that in Tests 2 and 3
the skin under the
sheets was dry. This likely was due to the lower MVTR of the plastic film in
Test 1 than the
barrier films in Tests 2 and 3. It was also observed that some shiny residue
was left on the
skin in Test 2, likely because the TC and PVA on the barrier film were
transferred to the skin
during the application. All three skin areas were deeply numb.
At t = 3 hours, all three skin areas were deeply numb.
At t = 5 hours, all three skin areas were numb.
At t = 5.5 hours, all three skin areas were numb, but the profoundness of the
numbing
is decreasing in all three skin areas.
At t = 6 hours, all three skin areas were slightly numb, but most of the skin
anesthesia
was gone.
[0216] These results suggest that: (1) a fabric coated with TC and PVA can be
an
independent product, which can be used with a commonly available plastic film
(a common
kitchen item in this case) and water to produce skin anesthesia. (2) TC and
PVA can be
coated to a barrier film without a fabric layer, and such a coated barrier
film can produce
good skin anesthesia. However, it may leave TC/PVA residual on the skin
because the TC
and PVA were not "fastened" to the sheet, as in sheets in which the TC and PVA
are
impregnated in the fabric layer. (3) The Ahlstrom SX567 polyester fabric can
be a good
fabric layer in the fabric-barrier film laminated sheet.
Example 36
[0217] A viscous aqueous solution (1.6% carbopol 981 NF, 0.9% sodium
hydroxide, 97.5%
water) was made and placed into a plastic squeeze bottle with a long
dispensing nozzle (1/2
oz. volume oval plastic bottle with "Yorker spout" cap, purchased from
Industrial Container
and Supply Co., Utah). A drop of the viscous solution was squeezed out of the
bottle onto
the skin of the back side of a human subject's hand. The drop of the viscous
solution was
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spread into a thin layer with the long nozzle of the squeeze bottle to cover
an area slightly
larger than I cm x 2 cm. A 1 cm x 2 cm piece was cut from a previously made TC
and PVA
impregnated laminated sheet (0.5 mg TC and 2.7 mg PVA per cm2 dried on the
Dusoft 84148
fabric pre-heat laminated on the MedCo RTS 1716-11 polyurethane film) and
placed on the
wet skin. After 60 min, the sheet piece was removed from the skin. The skin
was deeply
numb and dry. The sheet piece adhered very well to the skin during the entire
60 min
application time.
[0218] In applications in which the liquid (in the Sheet Liquid Combination
System) has to
be placed precisely (e.g. close to eyes), spraying the liquid on the skin may
not be adequate
because it can be difficult to aim the liquid when spraying. The sprayed
liquid may also run
because liquid that can be sprayed typically must have low viscosity. In those
applications, as
shown in this Example, viscous liquid can be applied with a squeeze bottle or
other
convenient (may be disposable) container with an applicator (e.g. the long
nozzle in this
case). The sheet can then be applied over the liquid layer.
Example 37
[0219] The following experiment was conducted to demonstrate the effect of
barrier film
(MVTR control layer) on a sheet's ability to produce skin anesthesia.
[0220] Step 1. A tetracaine (TC) loading solution with the following
composition was made:
0.7% tetracaine base, 11.2% of a 25% PVA:75% water solution, 88.1% rubbing
alcohol. The
density of the solution was about 0.91.
[0221] Step 2. Fifteen mL of the TC loading solution made in Step 1 was evenly
dispensed
onto a piece of fabric (190 cm2, single ply, Dusoft 84148) resting on a
release liner. The
solution soaked fabric was placed into an oven with a temperature of about 155
F for 40
minutes to evaporate off the solvents. The dried fabric had about 0.5 mg TC
and 2 mg PVA
per cm2.
[0222] Step 3. A drop of a viscous aqueous solution (1.6% Carbopol 981 NF,
0.9% sodium
hydroxide, 97.5% water) was squeezed out of a squeeze bottle and spread, with
the help of
the long nozzle of the squeeze bottle, onto a forearm skin area (slightly
larger than 1 cm x 2
cm) of a human subject. A 1 cm x 2 cm piece was cut from the dried fabric
produced in Step
2 (loaded with 0.5 mg TC and 2 mg PVA per cm2) and placed on the wet skin.
[0223] Step 4. In a separate skin area of the same forearm, the procedure in
Step 3 was
repeated, except that the dried fabric was laminated with the 3M9832
polyurethane tape,
using the tape's adhesive, just before the test.
cr
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Observations:
[0224] The piece of the fabric in Step 3 became visibly wet right after it was
placed on the
wet skin. The viscous solution easily penetrated the fabric layer, and could
be removed
(partially) if touched by a finger (the solution was not touched during this
test so it was not
removed). The fabric in Step 3 became visibly dry at t = 10-15 min (t = 0 was
when the sheet
was applied) and stayed on the skin very well until it was removed from the
skin at t = 60
min. The skin under the fabric in Step 3 was not numb at all at t = 60 min,
and not numb at all
in the next 6 hours.
[0225] At t = 60 min, the laminated sheet in Step 4 was removed and the skin
treated by it
was deeply numb. The skin area was dry but the fabric part of the sheet piece
was still a little
damp.
[0226] In the above experiment, water was present for about 10 minutes on the
skin area
under the fabric without a barrier film (by visual observation of dryness),
and for about 60
minutes under the laminated sheet. It is a little surprising that this
difference in the water
presence time produced such a dramatic difference in skin anesthesia: no
anesthesia at all vs.
deep anesthesia.
[02271 The above results reveal the importance of keeping water on the skin
for a long
enough time to obtain the anesthetic effect with tetracaine. Keeping water for
10 minutes or
less (as measured by visual observation of dryness) may be insufficient for
obtaining skin
anesthesia, at least in some individuals and under some conditions.
[0228] It should be pointed out that barrier film-fabric laminate may not be
the only
configuration in the sheet and liquid combination system of the current
invention that can
keep water on the skin for a long enough time to produce skin anesthesia. It
is possible that a
fabric with low enough MVTR, without a barrier film, may also be able to keep
water on the
skin for a sufficient period of time. It is also possible that a barrier film
impregnated with
tetracaine, without a fabric layer, can keep the water on the skin surface for
long enough time
(Example 38).
Example 38
[0229] The following attempt was made to impregnate TC into a polyurethane
film, so the
TC impregnated film alone could function as the sheet in the Sheet Liquid
Combination
system of the current invention.
[0230] One-tenth of a gram of tetracaine base (TC) was placed into a small
glass vial. A 2 cm
x 8 cm piece of a polyurethane film (MedCo RTS 1717-11, plastic carrier
removed) was also
placed into the glass vial. One and six-tenths grams of rubbing alcohol was
then added into
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the glass vial. After gentle shaking and waiting, all TC particles dissolved
in the rubbing
alcohol. The entire polyurethane film was submerged in the solution.
[0231] The above system was let sit in room temperature for 48 hours before
the
polyurethane film was retrieved from the solution. The retrieved film was
rinsed with water,
dried with a Kleenex paper tissue, and placed into an oven with temperatures
of about 155 F
for 30 minutes to evaporate off any solvent still in the film.
[0232] A thin layer of a viscous aqueous solution (1.6% Carbopol 981 NF, 0.9%
sodium
hydroxide, 97.5% water) was spread on the back side of a human subject's hand.
A 1 cm x 2
cm piece of the dried film was applied onto the wet skin. After a 60 min
application period
(during which the film stayed adhered to the skin surface very well), the film
was removed
from the skin. The skin area treated by the film was deeply numb. The skin
surface was still
wet when the film was removed, which was probably due to the fact that this
film is thicker
(thus probably had lower MVTR) than some other barrier films used in previous
tests (e.g.
3M9832F, MedCo RTS1716-11).
[0233] The above experiment reveals that a polyurethane film can absorb enough
TC (when
submerged in a TC solution) and can release TC at fast enough rate (when in
contact with the
appropriate vehicle solution) to anesthetize the skin within 60 min. Other
barrier films,
especially the ones of absorbent materials such as silicone and latex, may be
able to do the
same.
[0234] In this case, the sheet in the Sheet and Liquid Combination System was
the film
alone, impregnated with tetracainc. The adhesion agent (Carbopol 981 NF, pH
neutralized
with sodium hydroxide) was in the vehicle liquid. No fabric layer was used.
Alternatively, an
adhesion agent, such as PVP or PVA, can be placed in the drug solution and
impregnated into
the film via the same diffusion process for impregnating the drug (TC in this
case) into the
film.
Example 39
Skin Anesthesia Test for Sheets That Experienced Long Time High Temperature
Storage,
Were Made with Various Lamination Adhesives, Were Heat Laminated, etc.
[0235] The following samples were made for skin anesthesia tests:
Sample 1
[0236] 0.5 mg TC (tetracaine) and 2 mg PVA (polyvinyl alcohol) per etn2 was
impregnated
into the Dusoft 84148 fabric by a process as previously described. The loaded
fabric (dried)
was laminated to the 3M 9832 polyurethane tape using the tape's adhesive. The
laminated
sheet was stored in an oven with temperatures cycling between about 62 C and
about 68 C
S'l
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for 43 days. The fabric part (impregnated with TC and PVA) of the sheet became
slightly
yellow due to the long storage time at such a high temperature.
Sample 2
[0237] 0.3 mg TC and 2 mg PVA per cm2 was impregnated into the Dusoft 84148
fabric by a
process as previously described. The loaded fabric (dried) was laminated to
the 3M 9832F
polyurethane film using 3M 1504 XL transfer adhesive. The laminated sheet was
stored at
room temperature for 37 days before the test.
Sample 3
[0238] Same was produced and stored under conditions similar to the sheet in
Sample 2,
except the 3M1524 transfer adhesive, instead of the 3M1504 XL transfer
adhesive, was used.
Sample 4
[0239] The Dusoft 84148 fabric was laminated to the MedCo RTS 1716-11
polyurethane
film by heat using a heat lamination process similar to that described
previously (heating
temperature of 380 F, heating duration of 3 seconds). 0.5 mg TC and 2 mg PVA
per cm2 was
impregnated into the fabric of the laminated sheet using a method described
previously. The
laminated sheet impregnated with the TC and PVA was stored in an oven with
temperatures
cycling between about 62 C and about 68 C for 12 days before the test.
Sample 5
[02401 0.5 mg TC and 2 mg PVA per cm2 was impregnated into the Dusoft 84148
fabric by a
process as previously described. The TC and PVA impregnated fabric (dried) was
laminated
the 3M9832F polyurethane film with a heat lamination process similar to that
described
previously. The heating temperature and duration was 330 F and 2 seconds,
respectively.
The TC and PVA impregnated laminated sheet was stored in an oven with
temperatures
cycling between about 62 C and about 68 C for 29 days before the test.
Sample 6
[0241] The Dusoft 84148 fabric was laminated to the 3M9832F polyurethane film
by heat
using a heat lamination process similar to that described previously. The
heating temperature
and duration was 330 F and 2 seconds, respectively. 0.3 mg TC and 2 mg PVA
per cm2 was
then impregnated into the fabric of the laminated sheet using a process
similar to that
previously described. The TC and PVA impregnated laminated sheet was stored in
an oven
with temperatures cycling between about 62 C and about 68 C for 33 days
before the test.
[0242] The following skin tests were conducted: fine water droplets were
sprayed onto the
skin of the back of a human subject's hand with a spray bottle. Each of the
six sheets, about 1
cm x 2 cm, was placed on the wet skin and removed after 60 minutes. All six
skin areas were
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dry when the sheets were removed. The numbness of each of the skin areas
treated by the
sheets was tested by poking the area with a straightened paper clip. The
results are
summarized in Table 3 below.
Table 3
Test Sample Sample Sample Sample Sample Sample
Time* 1 2 3 4 5 6
60 min deeply deeply Not deeply Not Not
numb numb numb numb numb numb
120 deeply deeply deeply deeply deeply Not
min numb numb numb numb numb numb
240 numb numb Not numb Not Not
min numb numb numb
*Test time = 0 when the application of the sheets started
102431 These results suggest that:
02441 (1) The sheet with the configuration and formulation exemplified by
Sample 1 has
very stable anesthetizing ability. Storing the sample at about 62 C and 68 C
for 43 days
accelerated the aging of the sample so much that the fabric started to yellow,
yet the
anesthetizing ability of the sheet was not detcctably compromised. If one uses
the rule of
thumb that for every 10 C temperature increase, the rate of chemical or
physical process that
can (eventually) compromise the drug performance is increased by a factor of
3, the storage
conditions of about 62 C to about 68 C for 43 days is equivalent to storage
at 25 C for
approximately 10 years.
[02451 (2) Sample 2, the sheet with the 3M 1504XL transfer adhesive as the
lamination
adhesive, did not lose the anesthetizing ability after 37 days storage at room
temperature.
However, in a separate test, after the same sheet was stored at about 62 C to
about 68 C for
29 days, it did not produce numbness in a similar test. Without being limited
to any one
theory, it is possible that the 0.3 mg/cm2 TC quantity of the active
ingredient is sufficient to
provide only borderline effectiveness such that such sheets sometimes produce
the desired
numbness and sometimes do not. It is also possible that the 3m1504XL transfer
adhesive
slowly destroys the anesthetizing ability, so that the anesthetizing ability
of the sheet was
destroyed after 29 days at about 62 C to about 68 C but not lost after 37
days at about 25
C.
102461 (3) Sample 3, the sheet laminated with the 3M 1524 transfer adhesive,
had reduced
anesthetizing ability (not numb at t = 60 min but numb at t = 120 min) after
37 days storage at
room temperature. In a separate test, the same sheet that was stored at a
temperature of about
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62 C to about 68 C for 29 days, and when tested under similar conditions to
those spelled
out above, did not produce numbness. Again, without being limited to any one
theory, it is
possible that the 0.3 mg/cm2 TC quantity is of a dosage of active ingredient
so as to be
borderline effective such that such sheets sometimes produce numbness and
sometimes do
not. It is also possible that the 3M1524 transfer adhesive slowly destroys
anesthetizing
ability, so that the anesthetizing ability of the sheet was partially
destroyed after 37 days at 25
C. If the latter is the case, the 3M1524 transfer adhesive probably destroys
the anesthetizing
ability faster than the 3M1504 XL adhesive.
[0247] (4) Sample 4, a pre-heat laminated sheet comprising the film (MedCo RTS
1716-11
polyurethane) and the fabric (Derma Sciences Dusoft 84148 rayon-polyester
blend) with TC
and PVA impregnated in the fabric part, did not lose its anesthetizing ability
after 12 days of
storage at a temperature of about 62 C to about 68 C. Because the sheet does
not contain
lamination adhesive, its anesthetizing ability is expected to be very stable
over long term
storage because potential adverse interactions between the drug formulation
and the
lamination adhesive are avoided.
[0248] (5) For Sample 5, heating the TC and PVA impregnated fabric to 330 F
for 2
seconds in the heat lamination process and storing the laminated sheet at a
temperature of
about 62 C to about 68 C for 29 days significantly reduced, but did not
completely destroy,
the anesthetizing ability of the sheet.
[0249] For sample 6, the pre-heat laminated sheet impregnated with 0.3 mg TC
and 2 mg
PVA per cm2 lost all its anesthetizing ability after 33 days of storage at a
temperature of
about 62 C to about 68 C. Again, it is possible that the 0.3 mg/cm2 TC
quantity is
insufficient to be consistently effective such that such sheets sometimes
produce numbness
and sometimes do not. It is also possible that the 33 day high temperature
storage reduced the
originally already marginal anesthetizing ability to the level that it cannot
produce skin
anesthesia.
[0250] In this and other Examples, when a sheet that was stored at elevated
temperatures of
at least 45 C before testing for its anesthetizing ability, the duration of
storage of the sheet at
room temperature is typically not mentioned. That is because the physical or
chemical
process that reduces or destroys anesthetizing ability usually takes place at
a much faster rate
at the elevated temperatures than at room temperature, such that the duration
of room
temperature storage is insignificant.
Example 40
[0251] The following samples were made for skin anesthesia tests:
A
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[02521 Step 1. A blank loading solution was made by mixing 18.6 parts of a 25%
PVA:75%
water solution with 81.4 parts of rubbing alcohol. The density of this blank
loading solution
was about 0.91.
[0253] Step 2. TC Loading Solution A was made by dissolving 1.04% of
tetracaine base
(TC) in 98.96% of the blank loading solution made in Step 1. Twelve mL of the
TC Loading
Solution A was dispensed onto a fabric (190 cm2, Dusoft 84148 rayon-polyester
blend fabric
from Derma Sciences) resting on a release liner.
[0254] Step 3. TC Loading Solution B was made by mixing the TC Loading
Solution A
made in Step 2 with an equal weight of the blank loading solution made in Step
1. Twelve
mL of the TC Loading Solution B was dispensed onto a 190 cm2 of the same
fabric as in Step
2 resting on a release liner.
[0255] Step 4. TC Loading Solution C was made by mixing the TC Loading
Solution B
made in Step 3 with an equal weight of the blank loading solution made in Step
1. Twelve
mL of the TC Loading Solution C was dispensed onto a 190 cm2 of the same
fabric as in Step
2 resting on a release liner.
102561 Step 5. The three solution soaked fabric sheets made in Steps 2-4 were
dried in an
oven at a temperature of about 155 F for 60 min. The dried fabric sheets
contained 0.6 mg
TC + 2.7mg PVA/cm2, 0.3 mg TC + 2.7mg PVA/cm2, and 0.15 mg TC + 2.7mg PVA/cm2,
respectively.
[0257] Step 6. Each of the TC+PVA impregnated fabric pieces made in Step 5 was
laminated to the 3M9832 polyurethane tape using the tape's adhesive.
[0258] Step 7. The following skin anesthesia tests were conducted immediately
after Step 6:
fine water droplets were sprayed onto the skin of the back side of a human
subject's hand. A
piece, about 1 cm x 2 cm, was cut from each of the laminated sheets made in
Step 6 and
placed on the wet skin. After 45 minutes (t = 45 min), each sheet was lifted
and the skin area
was scratched with the end of a straightened paper clip to test the degree of
numbness
(anesthesia) induced by the sheet. The sheets were then replaced on the
original skin area and
kept there until t = 60 min, when all three sheets were removed. The degree of
skin anesthesia
in the three skin areas treated by the sheets was tested with the same
straightened paper clip
at several later time points. The skin numbness results are summarized in
Table 4 below.
Table 4
Time (from 0.15 mg TC/cm2 0.3 mg TC/cm2 0.6 mg TC/cm2
the start of
application)
Cl
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45 min Not numb Numb in most of Numb in entire
the area, but not area
entire area.
60 min Not numb Numb Numb
120 min Numb Numb Numb
300 min Numb Numb Numb
Remarks:
[0259] In this polyurethane film-rayon/polyester blend laminated sheet, 0.15
mg TC/cm2
produced delayed anesthesia effect (compared with the sheet containing 0.6 mg
TC/cm2). 0.3
mg TC/cm2 was better, but still not as good as 0.6 mg TC/cm2. Because it is
believed that
different individuals can have 3-4 fold difference in skin permeability, and
different skin
conditions (cold vs. warm, hydrated vs. dry) can also cause difference in skin
permeability,
0.6 mg TC/cm2 or higher TC quantity per cm2 should be used in a product so
that the product
can produce the desired effect in most users.
[0260] With a "lighter sheet", such as a polyurethane film impregnated with TC
without a
fabric layer, the amount of TC per cm2 needed to produce a maximum degree of
skin
anesthesia can be lower, because a lower amount of TC may be held by such a
'lighter" sheet
than the sheets used in the above tests.
Example 41
[0261] With methods similar to that described previously, 3 Dusoft 84148
fabric sheets were
loaded with the following amounts of PVA, respectively:
Fabric sheet A: 2 mg PVA/cm2
Fabric sheet B: 6.2 mg PVA/cm2
Fabric sheet C: 10 mg PVA/cm2
[0262] Each of the PVA-loaded fabric sheets (after drying) was laminated with
the 3M 9834
(polyurethane) tape, using the tape's adhesive. The fabric's side that faced
up during the
drying process was the side that adhered to the tape's adhesive layer.
[0263] A 2.5 cm x 4 cm piece was die cut from each of the laminated sheets
above. Water
was sprayed on the forearm skin of a human subject to form densely populated
water beads
on the skin. Each of the 2.5 cm x 4 cm sheets was applied on the wet skin, and
the sheets and
surrounding skin areas were gently tapped with a Kleenex tissue to ensure good
contact and
remove excess water on the skin. The human subject did routine lab work in the
next two
hours of test period so the skin areas were stretched and bent accordingly.
The sheets'
adhesion to the skin was observed for the two 2 hour test periods, with the
following results:
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[0264] Right after the sheets were applied ( t = 0): all sheets adhered to
skin well.
[0265] At t = 20 min: the 2 mg PVA/cm2 sheet had wrinkles and was partially
separated from
the skin. The 6.2 mg PVA/cm2 and 10 mg PVA/cm2 sheets stayed adhered well to
the skin.
[0266] At t = 70 mm: the 2 mg PVA/cm2 sheet had wrinkles and was about 40%
separated
from the skin. The 6.2 mg PVA/cm2 and 10 mg PVA/cm2 sheets stayed adhered well
to the
skin.
[0267] At t = 120 mm: all three sheets were removed from the skin. The 2 mg
PVA/cm2 sheet
had wrinkles and was about 50% separated from the skin just before removal.
The part that
was still adhered to the skin had post-it sticker kind of adhesion strength.
The 6.2 mg
PVA/cm2 and 10 mg PVA/cm2 sheets stayed adhered to the skin well until their
removal.
Peeling those two sheets off the skin lifted the skin slightly. Their adhesion
strength was
much stronger than that of the 2 mg PVA/cm2 sheet. The adhesion strength of
the 10 mg
PVA/cm2 sheet was not much stronger than the 6.2 mg PVA/cm2 sheet.
[0268] These results suggest that amounts of PVA higher than 2 mg/cm2 or about
6 mg/cm2
may make the sheet to have stronger adhesion to the skin. However, for
applications in which
the skin area is not expected to be bent or stretched, such as facial skin
anesthesia before
painful procedures, strong adhesion may be unnecessary and 2 mg PVA/cm2 may
provide
strong enough adhesion.
[0269] In another experiment, 10 mg PVA/cm2 and 0.5 mg tetracaine/cm2 was
loaded to a
Dusoft 84148 fabric with a method similar to that described previously. The
PVA and
tetracaine-loaded fabric sheet was laminated with the 3M 9832 tape, using the
tape's
adhesive. The fabric's side that faced up during the drying process was the
side that adhered
to the tape's adhesive layer. A 1 cm x 2 cm piece was cut from the laminated
sheet. Water
was sprayed on the forearm skin of a human subject to form densely populated
water beads
on the skin. The 1 cm x 2 cm sheet was applied on the wet skin, and the sheet
and
surrounding skin area were gently tapped with a Kleenex tissue to ensure good
contact and
remove excess water on the skin. The sheet adhered to the skin very well
during the entire 45
min test period. At 45 mm from the application, the sheet was removed from the
skin. Peeling
the sheet off the skin lifted the skin slightly. The skin was deeply numb and
dry when the
sheet was removed. No visible residue was left on the skin. These results
suggest that the
laminated sheet with the 10 mg PVA and 0.5 mg tetracaine/cm2 formulation can
successfully
anesthetize the skin.
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Example 42
[0270] Local anesthetic agent lidocaine and anti-infection agent chlorhexidine
are both
loaded into a polyurethane film using the method similar to that in Example
38. When this
lidocaine and chlorhexidine loaded film is applied to cover a wound surface,
such as a fresh
and severe burn wound surface, the bodily fluid from the wound surface would
contact the
film and the drugs lidocaine and chlorhexidine can be released from the film
using the bodily
fluid as the diffusion vehicle. This approach can achieve several benefits:
minimize the pain
(lidocaine's function), reduce the infection potential (chlorhexidine's
function), and isolate
the wound surface from the external environment (the film's function) which
can further
reduce the potential of infection. This approach can be very useful in
emergency situations,
such as war act-caused injuries, where the thorough treatment of the wound
cannot be
performed immediately and reducing the infection potential and pain for a few
hours before
the thorough treatment with a very simple method is very important.
[0271] In this Example, the "liquid" in the "sheet and liquid combination"
system of the
current invention is the bodily fluid oozing out of the wound. If that's not
enough fluid, a
water containing fluid can be sprayed on the wound surface or film as
additional "fluid".
[0272] A polyurethane film is particularly suitable for this purpose. A
polyurethane film with
proper thickness, such as 1/1000 inch or 1/2000 inch, can be a barrier to
viruses and bacteria .
while "breathable" to water vapor so that the wound surface is not completely
occluded
which can mean more comfort to the patient. More important, as shown in
Example 38, a
polyurethane film can absorb sufficient drug and release it at sufficient rate
to achieve a
therapeutic effect. While the drug in Example 38 is a local anesthetic, the
polyurethane film
should be able to absorb and release many other drugs with sufficient amounts
and rates.
[0273] It will be appreciated by those having skill in the art that many
changes may be made
to the details of the above-described embodiments without departing from the
underlying
principles of the invention. The scope of the present invention should,
therefore, be
determined only by the following claims.
4A
